Recommendations for the management of low-density lipoprotein cholesterol (LDL-C) and the strategy of statin therapy differ between current guidelines. We performed a prospective cohort study using data from the National Health and Nutrition Examination Survey from 1999 to 2010. For all-cause, cardiovascular, and noncardiovascular mortalities, we used Cox proportional hazards models to analyze unadjusted and multivariable-adjusted hazard ratios (HRs). We included age, gender, race and ethnicity, educational attainment, smoking status, body mass index, previous history of cardiovascular disease and cancer, diabetes, hypertension, LDL-C levels, high-density lipoprotein cholesterol levels, log-transferred triglyceride levels, estimated glomerular filtration rate levels, and the presence or absence of macroalbuminuria for the adjustment. The present study included 1,500 patients with LDL-C levels of <120 mg/dl (mean LDL-C level 88.7 mg/dl) who were at high risk of cardiovascular disease. A total of 99% patients completed the follow-up. Using multivariable Cox proportional hazards models, all-cause mortality was significantly lower in patients receiving statins than in those not on statins (HR 0.62, 95% confidence interval 0.45 to 0.85, p = 0.004). Analyses limited to propensity score-matched patients and patients with LDL-C levels of <100 mg/dl (mean LDL-C level 78.6 mg/dl) showed similar results. All-cause mortality in patients receiving statins was not significantly lower in those with LDL-C levels of <70 mg/dl than in those with LDL-C levels of 70 to 120 mg/dl (HR 1.27, 95% confidence interval 0.76 to 2.10, p = 0.35). In conclusion, statin therapy was effective in reducing all-cause death in high-risk patients, even with low levels of LDL-C. All-cause mortality did not differ between patients receiving statins with lower levels of LDL-C.