Abstract: Clinical trials of psychotherapy require diagnostic homogeneity, which implies a convergence of clinical presentations. Yet research study patients present diversely, and patients who do not fit a treatment paradigm may greatly complicate delivery of the study psychotherapy. The research literature has not addressed this issue. The authors use case illustrations of three psychotherapies – Prolonged Exposure, Relaxation Therapy, and Interpersonal Psychotherapy – from an ongoing psychotherapy outcome trial of posttraumatic stress disorder to describe psychotherapeutic responses to complex, “atypical” patients who strain standard treatment paradigms. Therapists required flexibility, and occasionally deviations from strict protocol, in treating heterodox patients. Such heterogeneity of presentation may have implications for psychotherapy outcome in research trials. Despite lack of discussion in the literature, many trials may face such issues.