Objective: Noninterventional, naturalistic studies facilitate examination of current clinical practices and provide an understanding of the impact of the biopsychosocial aspects of schizophrenia. This article describes disease burden and patient outcomes, with an emphasis on the comparative effectiveness and tolerability of antipsychotic monotherapy. Method: Outpatients initiating or changing antipsychotic therapy for DSM-IV- or ICD-10-defined schizophrenia (N = 7658) were allocated to olanzapine or nonolanzapine cohorts (November 2000 to December 2001). Treatment was at the psychiatrist's discretion, including flexible dosing and use of concomitant therapies and medications, with assessments at 0, 3, 6, 12, 18, 24, 30, and 36 months. Longitudinal clinical, pharmacologic, functional, and social data were collected over 36 months across 27 countries. Results: At entry, 76% of patients were initiated/ switched to antipsychotic monotherapy, most commonly with olanzapine (N = 3222), risperidone (N = 1117), quetiapine (N = 189), or haloperidol (N = 257). Patients prescribed olanzapine were more likely to maintain their baseline monotherapy (p < .001) and did so for a longer period (p < .001) compared with other antipsychotics. Median time to discontinuation (in months) was as follows: olanzapine 30.0, risperidone 23.1, quetiapine 13.9, haloperidol 12.5. Olanzapine-treated patients were also more likely to respond, and did so more rapidly than patients on other monotherapies (p < .001). Response data were also favorable for risperidone; median time to response (in months) was as follows: olanzapine 5.2, risperidone 6.3, quetiapine 11.3, haloperidol 11.7. Treatment-emergent adverse events varied: olanzapine patients had less favorable odds for significant weight gain (p < .001); haloperidol patients, for motor dysfunction (p ≤ .002). Conclusion: These naturalistic data from lessstudied outpatient communities highlight the variability in clinical and functional outcomes associated with long-term antipsychotic treatment.