In hypercholesterolemia significant changes in the nucleotide pattern of erythrocytes and lymphocytes as determined by high performance liquid chromatography were found. The decrease in ATP of lymphocytes in hypercholesterolemia from 10.4 +/- 0.3 to 7.0 +/- 0.4 nmol mg-1 protein (n = 8) was associated with an increase in ADP from 2.2 +/- 0.2 to 4.0 +/- 0.2 nmol mg-1 protein (P less than 0.005). The pattern of guanosine phosphates likewise was found to be changed in hypercholesterolemia. Akin to lymphocytes, red blood cells displayed marked changes in nucleotide levels. No such changes were observed in platelets. Cultured lymphocytes incubated with human plasma low density lipoproteins (LDL) (140 mg cholesterol dl-1) displayed a reversible fall in ATP and an increase in ADP by about 40% and 160%, respectively, with high density lipoproteins (HDL) or very low density lipoproteins (VLDL) being essentially ineffectual. It is concluded that in hypercholesterolemia a significant change in the nucleotide pattern of blood cells is exerted by the increase in LDL. Possible pathophysiological implications are discussed.