In patients with treatment-resistant schizophrenia (TRS), this study compared the efficacy of continuation treatment with flupenthixol alone, continuation electroconvulsive therapy (ECT) alone, and combined continuation ECT and flupenthixol. One hundred fourteen TRS patients received acute treatment (Phase I) with bilateral ECT and flupenthixol (12-24 mg/day). Fifty-eight patients met remitter criteria, including clinical stability during a 3-week stabilization period, and were eligible for the continuation treatment study (Phase II). Fifty-one patients enrolled in the single-blind Phase II continuation trial, and were randomized to the three treatment groups. The duration of the Phase II study was 6 months. Assessments of outcome included the Brief Psychiatric Rating Scale, Global Assessment of Functioning, and the Mini-Mental State Examination. Forty-five patients either relapsed or completed the Phase II study, and six patients dropped out. Among completers, 6 of 15 (40%) patients relapsed in the combined continuation ECT and flupenthixol group. In both the group treated with continuation ECT alone and that with flupenthixol alone, 14 of 15 (93%) patients relapsed. Analyses of intent-to-treat and completer samples demonstrated a marked advantage for the combination treatment condition in relapse prevention. Furthermore, all eight patients who received maintenance ECT combined with neuroleptic medication (Phase III study) maintained therapeutic benefits during the follow-up period of 3-17 months after the continuation treatment study. Among TRS patients who respond to acute combination treatment with ECT and neuroleptic therapy, continuation of this combination treatment is more effective in relapse prevention than use of ECT or neuroleptic therapy alone.