Objectives To determine the relationship between non–high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. Background Non–HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Methods Randomized placebo or active-controlled trials were evaluated. The effect of mean non–HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Results Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non–HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non–HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Conclusions Non–HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an ≈1:1 relationship between percent non–HDL-C lowering and CHD reduction.