Individuals with low serum cholesterol experience greater than expected age-adjusted mortality from non-atherosclerotic diseases, including cancer, respiratory and digestive illnesses, but the basis for these associations remains unclear. The current investigation considered the hypothesis that hypocholesterolemia is associated with reduced antioxidant reserve. Serum total antioxidant activity as well as concentrations of vitamin E, vitamin C, and thiols were compared in two groups of 24 subjects distinct in both mean low density lipoprotein (LDL) cholesterol (2.3 v. 4.9 mM) and mean total cholesterol (4.3 v. 7.0 mM). The low and high cholesterol groups were equivalent in gender mix, age, weight, and serum total protein. Results reveal that compared with the high group, the low cholesterol group had decreased total serum antioxidant activity (p<.05). Thiol concentrations were also lower in the low cholesterol group (p<.05). Group differences in serum total antioxidant activity and thiol concentration were larger among men than women. The two groups did not differ in vitamin C. Low cholesterol was associated with reduced absolute vitamin E levels, although the tocopherol: cholesterol ratio was the same in low and high cholesterol individuals. These data indicate that hypocholesterolemia may be associated with low serum antioxidant reserve, possibly increasing susceptibility to oxidative stress.