Objectives: Parkinson disease and dementia with Lewy bodies (collectively termed Lewy body disease) are common neurodegenerative conditions of later life and are frequently associated with distressing psychotic symptoms. The best approach to manage these symptoms is yet to be established and current treatments carry the risk of serious adverse effects. Methods: We performed a systematic review and meta-analysis of 19 randomized controlled trials investigating the efficacy of biological treatments for psychotic symptoms in Lewy body disease. Results: The summary effect estimate did not show a statistically significant benefit of biological treatments for psychotic symptoms in Lewy body disease (SMD −0.48, 95%CI −1.01 to 0.04). This was irrespective of the choice of intervention (SMD −0.53, 95%CI −1.20 to 0.14 for antipsychotic trials) or disease status (SMD −0.59, 95%CI −1.24 to 0.05 for trials of Parkinson disease). There was a significant effect for biological treatments compared with placebo in trials that lasted at least 6 weeks (SMD −0.25, 95%CI −0.43 to −0.08) and those with sample sizes greater than 100 participants (SMD of −0.28 95%CI −0.45 to −0.11). Conclusions: In this systematic review and meta-analysis, treatment of psychotic symptoms by biological means did not improve symptoms compared with placebo. Small sample sizes, modest treatment durations, and other methodological differences across the trials do make it difficult to draw firm conclusions. Longer, adequately powered trials utilizing established and novel treatments are needed to provide more definitive evidence to guide clinicians in the best choice of agent to treat these distressing and often persistent symptoms.