Declines in serum cholesterol have been reported in patients with altered immune system activity. However, the frequency and clinical significance of transient reductions in serum cholesterol after renal transplantation are unknown. In the present retrospective study, we examined the frequency and clinical setting of reduced serum cholesterol (≤4.40 mmol/L [170 mg/dL]) in patients who each had 28 ± 7 (total, 1,110) cholesterol determinations during the first year posttransplant. Reduced cholesterol was found on at least one occasion in 26 of 40 (65%) patients. Ninety-two percent (119/129) of the reduced cholesterol values occurred in one of three clinical settings: (1) within 10 days after transplantation, (2) within 6 weeks before or after the onset of acute rejection, or (3) within 6 weeks before or after the onset of a cytomegalovirus infection (CMV). Multiple linear regression analysis showed that the relationship between reductions in cholesterol associated with acute rejection was independent of CMV and the type of immunosuppression (one half of the patients were treated with cyclosporine [CSA]). The fact that serum albumin was reduced during CMV, but not during acute rejection, suggested that reduced cholesterol associated with rejection was relatively specific, and was not caused by a generalized leak of plasma proteins or by poor nutrition. Thus, during the first year posttransplant, reductions in serum cholesterol are most often associated with acute rejection episodes and/or CMV. The fact that the transient reductions in serum cholesterol occurred several weeks before and after the onset of clinical signs and symptoms suggests that a reduction in cholesterol could prove to be a useful marker of subclinical alterations in immune system activity after renal transplantation.