The plasma level of high density lipoprotein cholesterol (HDL-C) has been reported to be inversely correlated with the level of triglycerides (TGs) and the magnitude of postprandial lipemia because subjects with low HDL-C accompanying high TG levels often have an increased postprandial response to a fat load. However, information is limited regarding the postprandial response to a fat load in subjects with low HDL-C and normal fasting TG values (hypoalphalipoproteinemia [hypoalpha]). We administered an oral fat load (70 g/m2of body surface area) to six subjects with hypoalpha and six aged-matched control subjects. Plasma levels of lipids and lipoproteins and the mass of triglyceride-rich lipoproteins (TRLs: S, >100 and Sf20-100) were measured every 2 hours for 8 hours. The mass and chemical composition of Sr>100 or Sr20-100 TRLs were not different between the fasting groups; postprandial Sr> 100 but not Sr20-100 TRLs (mean±SD) was significantly lower in subjects with hypoalpha (200.4 ±64.8 mg/dL versus 110.6±50.9 mg/dL; analysis of variance,Ftest, p=0.04). In the hypoalpha subjects, the compositions of postprandial Sr> 100 TRLs were TG poor and cholesterol and phospholipid enriched (p<0.001) while the Sf20-100 TRLs were enriched in cholesterol and phospholipid but relatively protein depleted (p=0.002). When the hypoalpha subjects received gemfibrozil, the masses of both fasting (p=0.014) and postprandial (p=0.0004) Sf20-100 TRLs were lower compared with baseline, a response that was accompanied by partial normalization of composition in postprandial hypoalpha Sf20-100 TRLs. Our results indicate that in contrast to subjects with low plasma HDL-C and high TG levels, hypoalpha subjects with normal TG values did not display an increased postprandial response to fat feeding. Rather, the phenotype of hypoalpha appears to have a distinct metabolic component characterized by a reduced number of postprandial Sf> 100 TRLs of abnormal composition. Gemfibrozil reduced the mass and altered the composition of Sf20-100 TRLs in hypoalpha subjects.