Background Schizophrenia remains a major health problem despite antipsychotic medications that, for most patients, can decrease acute symptoms, decrease relapses, and contribute to partial and sometimes strong positive response in patients with chronic symptoms. What has not been clearbecause a double-blind, randomized, placebo-controlled trial is not feasible or ethicalis how many years after the initial episode, or onset of antipsychotic treatment, should medication be continued to achieve the best global outcome. We designed a small, clinical study to retrospectively perform a detailed follow-up to examine antipsychotic medication because it relates to both global outcome and life satisfaction. Methods This is a naturalistic study of 35 patients with chronic schizophrenia examining antipsychotic medication adherence from 8 to 50 years (average, 21 y) after onset of antipsychotic treatment. The sample was derived from all patients treated for many years in 1 physician's academic clinic. Most were treated by community physicians before referral to the academic clinic. Information was gathered on (1) medication adherence, (2) long-term global outcomes (based on both the patient ratings and a blind clinician's assessment [blind to medication data] on both the Global Outcome Scale and the Global Assessment of Functioning Scale), and (3) a patient-rated Satisfaction With Life Scale. Spearman rank order correlations were used to relate medication adherence to global outcomes and life satisfaction, as were linear regression models adjusted for demographic and clinical characteristics. Results A total of 35 patients (mean age, 45 y; mean years of possible medication since onset of treatment, 21 y) were assessed. Medication adherence was a statistically significant predictor of better long-term global outcomes and life satisfaction, both in Spearman rank order correlations and in covariate-adjusted linear regressions (all P values <0.01). Poor medication adherence was associated with poor outcomes, often disastrous, with low life satisfaction. Other variables such as presence of substance use disorders or family support did not explain the difference between those who adhered and those who did not. Conclusions In this naturalistic study, patients who adhered to antipsychotic medication had better long-term global outcomes than those who had poor adherence. Study limitations include the potential for residual confounding. This sample provides data consistent with the recommendation, in the absence of clinically important unwanted drug effects like tardive dyskinesia or large weight gain, for continuous, long-term antipsychotic treatment for chronic schizophrenia.