Background: There are over 300 Primary Immunodeficiency diseases (PID) that are a result of a genetic or idiopathic dysfunction of any aspect of the immune system. These conditions result in a higher frequency of infections, autoimmune conditions, or malignancies. Moderate intensity exercise is thought to help the immune system, while high intensity exercise may have a negative impact on immune function. The impact of exercise on individuals with an impaired immune system due to PID is not yet understood. Purpose: The purpose of this study was to investigate whether a low to moderate intensity exercise program would have an effect on stress, fatigue, and quality of life (QoL) for individuals diagnosed with PID. Methods: 34 participants were included in this eight-week, mixed-methods, randomized controlled trial, either as part of the control group, or as part of the exercise intervention group. Participants completed pre- and post-study outcome measures, reflective journaling, and a post-study interview. Results: There were no statistically significant differences between the groups for the outcome measures, infection incidence, or need for non-routine medical care. There was a clinically significant decline in the Physical Component Summary score of the SF-36v2 for the control group at the end of the study. The scores for the SF-36v2, for all participants, were below normative scores for all domains, at the beginning and end of the study. Four main themes emerged from the qualitative interviews: living with a ‘new normal’, the challenges of living with a chronic disease, facing the stigma of a chronic disease, and wanting to exercise, but were too exhausted to do so. Conclusions: Individuals with a diagnosis of PID have lower QoL scores as compared to population norms. They face high levels of stress, overwhelming fatigue, social isolation, and decreased emotional well-being. Exercise programs for this patient population did not result in increased infections or need for non-routine medical care but did result in emotional implications that need to be considered. Healthcare providers need to address emotional well-being and provide coping strategies. Exercise programs should be designed with a slow, methodical ramp-up to avoid increasing fatigue or stress, while exercise goals must be highly achievable and realistic. Physical therapists should collaborate with other healthcare professionals for a more holistic and interprofessional approach to working with patients with a diagnosis of PID.