Background: Maintenance chemotherapy is widely provided to patients with small cell lung cancer (SCLC). However, the benefits of maintenance chemotherapy compared with observation are a subject of debate. Methodology and Principal Findings: To identify relevant literature, we systematically searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. Eligible trials included patients with SCLC who either received maintenance chemotherapy (administered according to a continuous or switch strategy) or underwent observation. The primary outcome was 1-year mortality, and secondary outcomes were 2-year mortality, overall survival (OS), and progression-free survival (PFS). Of the 665 studies found in our search, we identified 14 relevant trials, which together reported data on 1806 patients with SCLC. When compared with observation, maintenance chemotherapy had no effect on 1-year mortality (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.66-1.19; P = 0.414), 2-year mortality (OR: 0.82; 95% CI: 0.57-1.19; P = 0.302), OS (hazard ratio [HR]: 0.87; 95% CI: 0.71-1.06; P = 0.172), or PFS (HR: 0.87; 95% CI: 0.62-1.22; P = 0.432). However, subgroup analyses indicated that maintenance chemotherapy was associated with significantly longer PFS than observation in patients with extensive SCLC (HR, 0.72; 95% CI: 0.58-0.89; P = 0.003). Additionally, patients who were managed using the continuous strategy of maintenance chemotherapy appeared to be at a disadvantage in terms of PFS compared with patients who only underwent observation (HR, 1.27; 95% CI: 1.04-1.54; P = 0.018). Conclusions/Significance: Maintenance chemotherapy failed to improve survival outcomes in patients with SCLC. However, a significant advantage in terms of PFS was observed for maintenance chemotherapy in patients with extensive disease. Additionally, our results suggest that the continuous strategy is inferior to observation; its clinical value needs to be investigated in additional trials.