The effectiveness of a novel 7-month psychosocial treatment designed to prevent the second episode of psychosis was evaluated in a randomized controlled trial at 2 specialist first-episode psychosis (FEP) programs. An individual and family cognitive behavior therapy for relapse prevention was compared with specialist FEP care. Forty-one FEP patients were randomized to the relapse prevention therapy (RPT) and 40 to specialist FEP care. Participants were assessed on an array of measures at baseline, 7- (end of therapy), 12-, 18-, 24-, and 30-month follow-up. At 12-month follow-up, the relapse rate was significantly lower in the therapy condition compared with specialized treatment alone (P = .039), and time to relapse was significantly delayed for those in the relapse therapy condition (P = .038); however, such differences were not maintained. Unexpectedly, psychosocial functioning deteriorated over time in the experimental but not in the control group; these differences were no longer statistically significant when between-group differences in medication adherence were included in the model. Further research is required to ascertain if the initial treatment effect of the RPT can be sustained. Further research is needed to investigate if medication adherence contributes to negative outcomes in functioning in FEP patients who have reached remission, or, alternatively, if a component of RPT is detrimental.