Few controlled trials compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs) regarding relapse prevention in schizophrenia. We conducted a systematic review/meta-analysis of randomized trials, lasting ≥6 months comparing SGAs with FGAs in schizophrenia. Primary outcome was study-defined relapse; secondary outcomes included relapse at 3, 6 and 12 months, treatment failure, hospitalization, and dropout due to any cause, non-adherence and intolerability. Pooled relative risk (RR) [+/−95%CIs] was calculated using random-effects model, with numbers-needed-to-treat (NNT) calculations where appropriate. Across 23 studies (n=4,504, mean duration=61.9+/−22.4 weeks), none of the individual SGAs outperformed FGAs (mainly haloperidol) regarding study-defined relapse, except for isolated, single trial-based superiority, and except for risperidone's superiority at 3 and 6 months when requiring >/=3 trials. Grouped together, however, SGAs prevented relapse more than FGAs (29.0% vs. 37.5%, RR=0.80, CI:0.70–0.91, p=.0007, I2=37%; NNT=17, CI:10–50, p=.003). SGAs were also superior regarding relapse at 3, 6 and 12 months (p=.04, p<.0001, p=.0001), treatment failure (p=.003) and hospitalization (p=.004). SGAs showed trend-level superiority for dropout due to intolerability (p=.05). Superiority of SGAs regarding relapse was modest (NNT=17), but confirmed in double-blind trials, first- and multi-episode patients, using preferentially or exclusively raw or estimated relapse rates, and for different haloperidol equivalent-comparator doses. There was no significant heterogeneity or publication bias. The relevance of the somewhat greater efficacy of SGAs over FGAs on several relevant outcomes depends on whether SGAs form a meaningful group and whether mid- or low-potency FGAs differ from haloperidol. Regardless, treatment selection needs to be individualized considering patient- and medication-related factors.