The aim of this study was to investigate the real-world effectiveness of antidepressant use in persons with schizophrenia. The register-based study cohort included all 61,889 persons treated in inpatient care due to schizophrenia during 1972–2014 in Finland. The main outcome was hospitalization due to psychosis and secondary outcomes included non-psychiatric hospitalization and all-cause mortality. We used within-individual design to compare the risk of hospitalization-based outcomes during the time periods of antidepressant use to antidepressant non-use periods within the same person, and traditional between-individual Cox models for mortality. The risk of psychosis hospitalization was lower during antidepressant use as compared to non-use (adjusted Hazard Ratio, aHR, 0.93, 95% CI 0.92–0.95). Antidepressants were associated with a decreased risk of mortality (aHR 0.80, 95% CI 0.76–0.85) and a slightly increased risk of non-psychiatric hospitalization (aHR 1.03, 95% CI 1.01–1.06). In conclusion, these results indicate that antidepressants might be useful and relatively safe to use in this population.