Background: Large-scale measles outbreaks in areas with high administrative vaccine coverage rates suggest the need to re-evaluate measles prevention and control in the Democratic Republic of Congo (DRC). Monitoring of measles Vaccine Effectiveness (VE) is a useful measure of quality control in immunization programs. We estimated measles VE among children aged 12–59 months in the Democratic Republic of Congo (DRC) using laboratory surveillance data from 2010–2012. Methods: We used the case-based surveillance system with laboratory confirmation to conduct a case-control study using the test negative design. Cases and controls were selected based on presence (n = 1044) or absence (n = 1335) of measles specific antibody IgM or epidemiologic linkage. Risk factors for measles were assessed using unconditional logistic regression, stratified by age. Results: Among children 12–59 months, measles vaccination was protective against measles [aOR (95% C)], 0.20 (0.15–0.26) and estimated VE was 80% (95% CI 74–85%). Year of diagnosis, 2011: 6.02 (4.16–8.72) and 2012; 8.31 (5.57–12.40) was a risk factor for measles when compared to 2010. Compared to Kinshasa, children in Bas-Congo, Kasai-Oriental, Maniema and South Kivu provinces all had higher odds of developing measles. Measles VE was similar for children 12–23 months and 24–59 months (80% and 81% respectively). Conclusions: Repeated occurrences of measles outbreaks and lower than expected VE estimates suggest the need to further evaluate measles vaccine efficacy and improve vaccine delivery strategies in DRC.