The aim of this exploratory study was to examine the possible mechanisms of behavioral change in a cognitive-behavioral intervention supporting medication adherence in HIV-infected persons. A total of 60 persons currently under medical treatment were randomized to psychotherapy or usual care and were compared with a sociodemographically matched group of general psychotherapy clients. Outcome measures included therapy adherence using medication event-monitoring system psychotherapeutic processes and changes of experience and behavior. The general psychotherapy group was initially more distressed than HIV psychotherapy patients and reached higher levels of psychotherapeutic effect. In the HIV psychotherapy patients, a significant effect was found for maintaining adherence to medical treatment (Weber et al., 2004). These findings show that psychotherapy is a beneficial intervention for HIV-infected persons, and therapeutic alliance and activation of resources do not differ from a general psychotherapy treatment. Differential effects were detected for specific process variables, namely problem actuation.