Extensive interdisciplinary common factor research has identified the therapeutic relationship as a consistent factor influencing therapeutic outcomes. We use Polyvagal and Interpersonal Neurobiology (IPNB) theories to guide an examination of the physiological mechanisms at work in the therapeutic relationship. Both Polyvagal and IPNB theories provide understandings about how humans are neurophysiologically wired for social connection. Each points to a sense of safety as being essential for meaningful connection to occur and clarifies that physiological attunement is an observable indicator of interpersonal connection. In this study, we use these theories to guide an examination of therapist physiological influence on clients in couple therapy, using continuous in-session data collection of respiratory sinus arrhythmia (RSA) for 22 heterosexual married couples and their therapist. Data were modeled in a multi-level path analytic framework to account for within-individual and within-couple effects. Results indicated that therapist RSA does not significantly predict lagged client RSA. A discussion of potential limitations, suggestions for therapists and recommendations for future study is included.