The objective of this study was to analyze the anti-inflammatory effect of minocycline in rheumatoid arthritis. Serum samples of 65 RA patients who completed a 26-week randomized double-blind trial of minocycline (100 mg twice a day) versus placebo were studied. In this trial some clinical parameters and in particular the acute phase response decreased significantly in the minocycline-treated group. Serum levels of albumin and interleukin-6 (IL-6) were compared with CRP levels in order to study the acute phase response. Furthermore, rheumatoid factor (RF) and total immunoglobulin isotypes as well as serum levels of soluble interleukin-2 receptor (sIL2-2R) were determined in order to study immunological parameters of the disease. Immunoglobulins and cytokines were measured by ELISA. Serum levels of albumin remained stable, whereas serum CRP levels decreased both in the minocycline- and in the placebo-treated group. Serum levels of IL-6 decreased in the minocycline-treated group only and this decrease was positively correlated with the decrease in CRP levels. Minocycline significantly decreased serum IgM-RF, IgA-RF, total IgM and total IgA levels. In addition the ratio of IgM-RF/total IgM decreased in the minocycline-treated group. No such changes were observed in the placebo-treated group. The anti-inflammatory effect of minocycline in RA patients may be due to the reduction in the synthesis of IL-6 and rheumatoid factor.