Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNFalpha, IL-1beta, and IL-6 and potentiate the expression of the antiinflammatory cytokine IL-10. We report a randomized, single-blind, placebo-controlled, crossover study of testosterone replacement (Sustanon 100) vs. placebo in 27 men (age, 62 +/- 9 yr) with symptomatic androgen deficiency (total testosterone, 4.4 +/- 1.2 nmol/liter; bioavailable testosterone, 2.4 +/- 1.1 nmol/liter). Compared with placebo, testosterone induced reductions in TNFalpha (-3.1 +/- 8.3 vs. 1.3 +/- 5.2 pg/ml; P = 0.01) and IL-1beta (-0.14 +/- 0.32 vs. 0.18 +/- 0.55 pg/ml; P = 0.08) and an increase in IL-10 (0.33 +/- 1.8 vs. -1.1 +/- 3.0 pg/ml; P = 0.01); the reductions of TNFalpha and IL-1beta were positively correlated (r(S) = 0.588; P = 0.003). In addition, a significant reduction in total cholesterol was recorded with testosterone therapy (-0.25 +/- 0.4 vs. -0.004 +/- 0.4 mmol/liter; P = 0.04). In conclusion, testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol. Twenty of these men had established coronary disease, and because total cholesterol is a cardiovascular risk factor, and proinflammatory cytokines mediate the development and complications associated with atheromatous plaque, these properties may have particular relevance in men with overt vascular disease.