OBJECTIVE: Effects of first in comparison with second-generation antipsychotics on the subjective quality of life (QoL) of patients with schizophrenia under routine treatment conditions were examined. METHOD: In a prospective naturalistic trial the QoL, social, clinical, and treatment-related characteristics and type of antipsychotic medication of 307 patients with schizophrenia (ICD-10 F 20) were assessed five times with 6-month intervals over 2.5 years. Longitudinal and cross-sectional effects of antipsychotic medication were assessed by hierarchical regression models. Selection bias was controlled by propensity scores. RESULTS: While positive effects of first-generation antipsychotics on subjective QoL in comparison with no antipsychotic treatment were found, second-generation antipsychotics caused no better QoL than first-generation antipsychotics. CONCLUSION: The hypothesis that second-generation in comparison with first-generation antipsychotics have a better effect on the improvement of subjective QoL of people with schizophrenia in routine out-patient treatment was not supported.