Plasma levels of HDL apo A-I are reduced in individuals with low HDL cholesterol (HDL-C) concentrations as a result of increased fractional catabolic rates (FCRs). To determine the basis for the high apo A-I FCRs, seven subjects with low HDL-C levels (31.0±4.3 mg/dl) were compared with three subjects with high HDL-C levels (72.0±4.5 mg/dl). Each subject received autologous HDL that was labeled directly by the iodinemonochloride method (whole-labeled) and autologous HDL that was labeled by exchange with homologous radiolabeled apo A-I (exchange-labeled). Blood was obtained for 2 wk, specific activities determined, and FCRs (d-'+SD) estimated. In every subject, whether in the low or high HDL-C group, the exchange-labeled FCR was greater than the whole-labeled FCR. The exchange-labeled FCR was higher in the low HDL-C group (0.339±0.043) versus the high HDL-C group (0.234 ±0.047; P < 0.009). The whole-labeled FCR was also greater in the low HDL-C group (0.239±0.023) versus the high HDL-C group (0.161±0.064; P < 0.02). In addition, in both low and high HDL groups ultracentrifugation resulted in more radioactivity in d > 1.210 (as percentage of total plasma counts per minute) with the exchange-labeled tracer than with the wholelabeled tracer (12.55±4.95% vs. 1.02±0.38%; P < 0.003). With both HDL tracers, more radioactivity was found in d > 1.210 in the low versus the high HDL-C groups. When apo A-I catabolism was studied by perfusing isolated rabbit kidneys with whole-labeled HDL, there was twice as much accumulation (cpm/g cortex) of HDL apo A-I isolated from subjects with low HDL-C than from subjects with high HDL-C (P < 0.0025). Finally, HDL that had been isolated from subjects with high levels of HDL-C was triglyceride enriched and exposed to partially purified lipases before perfusion through kidneys. Threefold more apo A-I from modified HDL accumulated in the cortex compared with the unmodified preparation (P < 0.007). The results of these in vivo and ex vivo studies indicate that individuals with low HDL-C levels have more loosely bound, easily exchanged apo A-I and that this exchangeable apo A-I is more readily cleared by the kidney. (J. Clin. Invest.