Accumulating evidence indicates that psychotherapy participants show increased physiological responsiveness to stress. The purpose of the present study was to examine differences between individuals participating in outpatient psychotherapy and matched controls using an experimental design. Forty-two psychotherapy participants and 48 matched controls were assessed on cardiovascular and cortisol functioning at baseline, during the Trier Social Stress Test (TSST), and during a 20-min recovery period. Psychotherapy participants and matched controls did not differ at baseline or during the TSST on the physiological measures but psychotherapy participants had higher cortisol and heart rate (HR) during the recovery period. In regards to reactivity, cortisol increased during the recovery period for the psychotherapy participants but decreased for those in the matched control group. Psychotherapy participants experiencing clinically significant levels of distress displayed elevated systolic and diastolic blood pressure and HR during the TSST when compared to psychotherapy participants not experiencing clinically significant levels of distress. Overall, physiological reactivity to stress appears to be an important issue for those in psychotherapy and directly addressing this issue may help improve psychotherapy outcomes.