Abstract: This study investigated whether illness progression and treatment refractoriness emerge after relapse in schizophrenia. We compared outcomes in a cohort treated with a standardized protocol for the first and second episodes of illness. The sample comprised 31 participants who (1) had successfully completed a 2-year open-label treatment phase with risperidone long-acting injection (RLAI) for a first episode of schizophrenia; (2) underwent an intermittent treatment extension phase up to 3 years or until recurrence, and (3) entered a further 2-year treatment phase with RLAI for a recurrence episode. For the patients who remained in treatment (n = 14 [45%]), Positive and Negative Syndrome Scale score reductions, response rates, remission rates, time to response, time to remission, functional outcome scores, and modal RLAI doses were similar for the 2 treatment periods. However, 17 (55 %) of the 31 patients discontinued the study in the second episode compared with 14 (28%) of 50 patients in the first episode, suggesting reduced effectiveness of antipsychotics when reintroduced after illness recurrence. Most notably, emergent treatment nonresponsiveness was observed in 5 participants (16%), consistent with the hypothesis that relapse may be biologically harmful in a subset of patients.