Background While antipsychotics are effective in the maintenance treatment of schizophrenia they have safety and tolerability risks. We investigated whether a combination of omega-3 polyunsaturated fatty acids (ω−3 PUFAs) and a metabolic antioxidant, alpha-lipoic acid (α-LA), is effective in preventing relapse after antipsychotic discontinuation in subjects who were successfully treated for 2–3years after a first-episode of schizophrenia, schizo-affective or schizophreniform disorder. Methods In this randomized, double-blind, placebo controlled study antipsychotic treatment was tapered and discontinued and participants received either ω−3 PUFAs (eicosapentaenoic acid 2g/day and docosahexaenoic acid 1g/day)+α-LA 300mg/day or placebo. Subjects were followed up for two years, or until relapse. Results Recruitment was terminated prematurely due to the high relapse rates in both treatment groups as well as the severity of some of the relapse episodes. Of the 33 participants, 19/21(90%) randomized to ω−3 PUFAs+α-LA relapsed and one (5%) completed two years without relapse (p =0.6); and 9/12 (75%) randomized to placebo relapsed and none completed two years without relapse. Mean times to relapse were 39.8±25.4 and 38.3±26.6weeks for the ω−3 PUFAs+α-LA and placebo groups, respectively (p =0.9). There were no significant differences between the groups in relapse symptom severity. Conclusions We found no evidence that ω−3 PUFAs+α-LA could be a suitable alternative to maintenance antipsychotic treatment in relapse prevention, in this small study. Antipsychotic discontinuation after a single episode of schizophrenia carries a very high risk of relapse, and treatment guidelines endorsing this practice should be revised.