High-density lipoprotein (HDL) cholesterol (HDL-C) levels are a strong inverse predictor of atherosclerosis risk, but the physiological determinants of HDL-C levels are poorly understood. We selected 57 human subjects (30 women and 27 men) with a broad range of HDL-C levels and performed turnover studies of apolipoprotein (apo)A-I and apoA-II, the two major apolipoproteins of HDL, to measure the fractional catabolic rate (FCR) and production or transport rate (TR) of these proteins. We also measured several other parameters known to correlate with HDL-C levels to test for their interrelations and to postulate mechanisms of regulation of HDL-C levels. As expected, the women had higher levels of HDL-C (56.7 +/- 21.4 versus 45.1 +/- 16.3 mg/dL, mean +/- SD; P = .03) and apoA-I (147 +/- 32 versus 126 +/- 29 mg/dL, P = .01) than men and did not differ in apoA-II levels (34.5 +/- 7.4 versus 33.3 +/- 7.5 mg/dL, P > .2). The FCR of apoA-I tended to be lower in the women (0.248 +/- 0.077 versus 0.277 +/- 0.069 pools/d, P = .1), although the difference was not statistically significant. The FCR of apoA-II was also lower (0.184 +/- 0.043 versus 0.216 +/- 0.056 pools/d, P = .02). In contrast, the apoA-I TR was equal in women and men (12.0 +/- 1.6 versus 12.1 +/- 2.8 mg/kg per day, P > .2), and there was a trend toward lower apoA-II TR in women (2.19 +/- .62 versus 2.61 +/- 1.06 mg/kg per day, P = .07). Linear regression analysis revealed a strong inverse correlation between HDL-C levels and the FCRs of apoA-I and apoA-II (r = -.81 and -.76, respectively; P < .0001 for both). In contrast, there was little or no association between HDL-C and the TRs of apoA-I and apoA-II (r = .06 and -.35, P = not significant and .01, respectively). In stepwise multiple linear regression analysis, apoA-I FCR alone accounted for 66% of the variability in HDL-C; two other variables accounted for an additional 7%. Due to the importance of apoA-I FCR, its determinants were sought among the remaining variables.(ABSTRACT TRUNCATED AT 400 WORDS)