It has been suggested that statins can both stimulate and suppress the immune system, and thereby, may influence autoimmune diseases. Therefore, we studied effects of statins on innate and adaptive immunity, and self-tolerance by measuring serological levels of C-reactive protein (CRP), neopterin, immunoglobulin E (IgE) antibodies and the presence of autoantibodies (antinuclear antibodies (ANA) and IgM rheumatoid factor (RF)) in the general population. We conducted a nested case-control study within the population-based Doetinchem cohort. Data from health questionnaires, serological measurements and information on medication from linkage to pharmacy-dispensing records were available. We selected 332 statin users (cases) and 331 non-users (controls), matched by age, sex, date of serum collection, history of cardiovascular diseases, diabetes mellitus type II and stroke. Multivariate regression analyses were performed to estimate effect of statins on the immune system. The median level of CRP in statin users (1.28 mg/L, interquartile range (IQR): 0.59-2.79) was lower than in non-users (1.62 mg/L, IQR: 0.79-3.35), which after adjustment was estimated to be a 28% lower level. We observed an inverse association between duration of statin use and CRP levels. Elevated levels of IgE (>100 IU/mL) were more prevalent in statin users compared to non-users. A trend towards increased levels of IgE antibodies in statin users was observed, whereas no associations were found between statin use and levels of neopterin or the presence of autoantibodies. In this general population sub-sample, we observed an anti-inflammatory effect of statin use and a trend towards an increase of IgE levels, an surrogate marker for Th (helper) 2 responses without a decrease in neopterin levels, a surrogate marker for Th1 response and/or self-tolerance. We postulate that the observed decreased inflammatory response during statin therapy may be important but is insufficient to induce loss of self-tolerance.