Statins possess anti-inflammatory and immunomodulatory properties beyond their cholesterol-lowering effects. To determine whether short-term atorvastatin treatment affects the acute phase and humoral immune responses to tetanus toxoid (TT) in normal healthy volunteers, we conducted a randomized, double blind, placebo-controlled trial. Twenty healthy volunteers were assigned a 10-day treatment with atorvastatin (40 mg) or placebo. All volunteers received a TT booster on the fifth day. Subjects in the atorvastatin group had a significant reduction in total and low-density lipoprotein cholesterol (both p<0.001). Unexpectedly, the production of anti-TT antibodies (predominately IgG1) was three-fold higher in the atorvastatin group 15 days post-vaccination (2306 +/- 468 versus 713+/-21 units, p = 0.008). Atorvastatin also suppressed the post-vaccination rise in platelet and lymphocyte counts (both p<0.05). Acute phase parameters did not change significantly in either group. This study illustrates a novel immunomodulatory effect of atorvastatin raising the possibility of using HMG-CoA reductase inhibitors to enhance humoral responses to vaccination.