Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.