OBJECTIVE The favorable effect of clozapine on psychotic symptoms in patients with treatment-resistant (TR) schizophrenia (SCZ) in short-term studies is well established. However, prospective studies of the long-term outcome of clozapine treatment on psychopathology, cognition, quality of life, and functional outcome in TR-SCZ are limited. METHODS Here, we have examined the long-term (mean duration of follow-up 14 years) effects of clozapine on those outcomes in a prospective, open label study in 54 TR-SCZ patients. Assessments were performed at baseline, 6 weeks, 6 months, and at the last follow-up. RESULTS Brief Psychiatric Rating Scale (BPRS) total, positive symptoms, and anxiety/depression at the last follow-up improved significantly from baseline, as well as from the 6-month evaluation ( P < 0.0001), with a 70.5% responder rate (≥20% improvement at the last follow-up from baseline). Quality of Life Scale (QLS) total improved by 72% at the last follow-up, with 24% of patients rated as having "good" functioning compared with 0% at baseline. Suicidal thoughts/behavior was significantly reduced at the last follow-up from the baseline. No significant change in negative symptoms was found at the last follow-up in the total sample. Short-term memory function declined at the last follow-up from baseline, but there was no significant change in processing speed. The QLS total showed a significant negative correlation with BPRS positive symptoms but not with cognitive measures, or negative symptoms, at the last follow-up. CONCLUSIONS For patients with TR-SCZ, improving psychotic symptoms with clozapine seems to have a more significant impact than negative symptoms or cognition on improving psychosocial function.