BACKGROUND: Prior studies have found inverse associations between high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I levels and cardiovascular disease (CVD). Whether this observation is consistent across low-density lipoprotein cholesterol (LDL-C) levels or total atherogenic particle burden (apolipoprotein B100) is less well-studied, particularly in women. OBJECTIVE: To determine the association between HDL-C or apolipoprotein A-I level and CVD across a range of LDL-C and apolipoprotein B100 values. DESIGN: Prospective cohort study. SETTING: The Women's Health Study, a cohort of U.S. female health professionals. PARTICIPANTS: 26,861 initially healthy women, aged 45 years or older at study entry (1992-1995), who were followed for a mean of approximately 11 years. MEASUREMENTS: Baseline lipids were measured directly, and apolipoproteins were measured with immunoassays. Outcomes were incident total CVD (n = 929), coronary events (n = 602), and stroke (n = 319). RESULTS: In multivariable analyses, HDL-C and apolipoprotein A-I levels were inversely associated with CVD and coronary events but not stroke. Adjusted coronary hazard ratios for decreasing quintiles of HDL-C were 1.00 (reference), 1.23 (95% CI, 0.85 to 1.78), 1.42 (CI, 0.98 to 2.06), 1.90 (CI, 1.33 to 2.71), and 2.19 (CI, 1.51 to 3.19) (P for linear trend < 0.001); corresponding hazard ratios for apolipoprotein A-I were 1.00 (reference), 0.98 (CI, 0.71 to 1.35), 1.02 (CI, 0.72 to 1.44), 1.37 (CI, 0.98 to 1.90), and 1.58 (CI, 1.14 to 2.20) (P for linear trend = 0.005). Consistent inverse associations were found for HDL-C with coronary events across a range of LDL-C values, including among women with low LDL-C levels. No associations were noted for HDL-C or apolipoprotein A-I among women with low apolipoprotein B100 values (<0.90 g/L). LIMITATION: Participants were at low risk for CVD, the number of events in the lowest apolipoprotein B100 stratum was small, only a single baseline measurement was obtained, and residual confounding may have occurred. CONCLUSION: Consistent inverse associations were found for HDL-C with incident coronary events among women with a range of LDL-C values. Among women with low total atherogenic particle burden (apolipoprotein B100 level <0.90 g/L), few events occurred and no associations were seen. PRIMARY FUNDING SOURCE: Merck & Co. and the National Heart, Lung, and Blood Institute and National Cancer Institute, National Institutes of Health.