Objectives We sought to assess the relationship between the magnitude of low-density lipoprotein cholesterol (LDL-C) lowering and rates of elevated liver enzymes, rhabdomyolysis, and cancer. Background Although it is often assumed that statin-associated adverse events are proportional to LDL-C reduction, that assumption has not been validated. Methods Adverse events reported in large prospective randomized statin trials were evaluated. The relationship between LDL-C reduction and rates of elevated liver enzymes, rhabdomyolysis, and cancer per 100,000 person-years was assessed using weighted univariate regression. Results In 23 statin treatment arms with 309,506 person-years of follow-up, there was no significant relationship between percent LDL-C lowering and rates of elevated liver enzymes (R 2 <0.001, p = 0.91) or rhabdomyolysis (R 2 = 0.05, p = 0.16). Similar results were obtained when absolute LDL-C reduction or achieved LDL-C levels were considered. In contrast, for any 10% LDL-C reduction, rates of elevated liver enzymes increased significantly with higher statin doses. Additional analyses demonstrated a significant inverse association between cancer incidence and achieved LDL-C levels (R 2 = 0.43, p = 0.009), whereas no such association was demonstrated with percent LDL-C reduction (R 2 = 0.09, p = 0.92) or absolute LDL-C reduction (R 2 = 0.05, p = 0.23). Conclusions Risk of statin-associated elevated liver enzymes or rhabdomyolysis is not related to the magnitude of LDL-C lowering. However, the risk of cancer is significantly associated with lower achieved LDL-C levels. These findings suggest that drug- and dose-specific effects are more important determinants of liver and muscle toxicity than magnitude of LDL-C lowering. Furthermore, the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer.