In this study, we analyzed the effectiveness of statin therapy for the primary prevention of cardiovascular disease (CVD) in low- and medium-risk patients. Using observational data, we estimated effectiveness by emulating a hypothetical randomized clinical trial comparing statin initiators with statin non-initiators. Two approaches were used to adjust for potential confounding factors: matching and inverse probability weighting in marginal structural models. The estimates of effectiveness were obtained by intention-to-treat and per-protocol analysis. The intention-to-treat analysis revealed an absolute risk reduction of 7.2 (95% confidence interval (CI95%), −6.6–21.0) events per 1000 subjects treated for 5 years in the matched design, and 2.2 (CI95%, −3.9–8.2) in the marginal structural model. The per-protocol analysis revealed an absolute risk reduction of 16.7 (CI95%, −3.0–36) events per 1000 subjects treated for 5 years in the matched design and 5.8 (CI95%, 0.3–11.4) in the marginal structural model. The indication for statin treatment for primary prevention in individuals with low and medium cardiovascular risk appears to be inefficient, but improves with better adherence and in subjectvs with higher risk.