Background: The experience of stress and anxiety in nursing students can reach a high level because of fear of making an error or causing fatal harm to a patient. Unmitigated stress and anxiety can hinder learning and the performance of psychomotor skills in the clinical setting, eventually affecting patient care.Aim: This study aimed to examine anxiety, stress, self-efficacy for nursing clinical skills, and self-efficacy for therapeutic communication in undergraduate nursing students who were randomized to either an intervention with a standardized patient or the comparison group who participated in role play. Method: An experimental study with randomization was conducted with prelicensure nursing students (N = 87) recruited from associate and bachelor’s degree nursing programs in the Finger Lakes region of New York State, using the State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS), Clinical Skills Self-Efficacy Scale (CSES), and Self-Efficacy in Therapeutic Communication (SETC). Data collection occurred at preintervention, postintervention, and at follow-up, approximately 2 weeks after the intervention. Results: The first report describes the development of the Self-Efficacy for Therapeutic Communication Scale (SETC) developed by the principal investigator and used in this study. Exploratory factor analyses with a Varimax rotation of the 15 items yielded two factors accounting for 51.3% of the variance. Two subscales were formed by summing the items loading above .4 on each factor. The first subscale was Communication Techniques, which included 9 items and had a Cronbach’s alpha of .91 The second subscale was Intuitive Practices with 6 items and a Cronbach’s alpha of .79. The correlation between the two subscales was r = .67 (p < .001). Test-retest reliability for the scale from pre- to posttest was .68, pre- to follow-up was .41, and posttest to follow-up was .68. In the second report, Pearson’s r was used to determine that state anxiety, trait anxiety, and stress were highly correlated with each other, with a range of correlations, r = .53 to .91, p < .001. Inverse contemporaneous correlations were found for trait anxiety and for stress with self-efficacy for clinical skills at all time points, whereas state anxiety was inversely related to self-efficacy for clinical skills at posttest and follow-up. Inverse correlations for self-efficacy for therapeutic communication were statistically significant with state anxiety, trait anxiety, and stress, but only at posttest. In the third report, mixed Analysis of Variances (ANOVAs) determined that there was a statistically significant interaction between time and group on state anxiety scores, F(2, 170) = 3.551, p = .031, η2 = .040. Simple main effects analyses showed that the intervention and comparison group means did not differ at any of the three testing times. Paired samples t tests indicated that the scores on anxiety in the intervention group did not show any statistically significant change over time, whereas anxiety in the comparison group was significantly higher at follow-up than at any other time. Mixed ANOVAs showed no interaction between time and groups for self-efficacy for clinical skills or for self-efficacy for therapeutic communication. Results indicated that the intervention and comparison group means on self-efficacy for clinical skills and self-efficacy for therapeutic communication improved over time. Both intervention and comparison groups reported increased self-efficacy in clinical skills and therapeutic communication at follow-up data collection. In addition, two separate mixed ANOVAs were performed to determine if stress had a moderating effect on the intervention. Students in the high stress group (PSS greater than 18), did not experience a change in anxiety over time, while the comparison group of participants with low stress (scores less than or equal to 18), had significant changes in anxiety from pretest to follow-up and posttest to follow-up, while the intervention group did not. Conclusion: Stress and anxiety can have detrimental effects on nursing students’ self-efficacy for clinical skills and self-efficacy for therapeutic communication. Prioritizing and mitigating the effects of stress and anxiety to improve self-efficacy in nursing students is one way of preparing nursing students for competency-based education, as outlined in the American Association of Colleges of Nurses, The Essentials: Core Competencies for Professional Nursing Education. Throughout the Domains of The Essentials, therapeutic communication is found in 13 competencies, indicating that this once considered soft skill, is a critical skill required for safe patient care. Teaching methods that include interactions with standardized patients and managing difficult conversations can be helpful for the nursing student to experience in pre-clinical preparation. Keywords: Anxiety, self-efficacy, standardized patients, therapeutic communication, clinical nursing skills