BACKGROUND The efficacy of the immune response upon vaccination in patients treated with anti-tumor necrosis factor-alpha (anti-TNF) with or without methotrexate is the subject of debate. We studied the effect of immunosuppressive treatment, including anti-TNF and methotrexate, on the response to pneumococcal polysaccharide (PPS) vaccine. METHODS Fifty-two patients treated with immunosuppressives including anti-TNF (anti-TNF group), 41 patients given a similar immunosuppressive regimen without anti-TNF (no anti-TNF group), and 18 healthy controls were vaccinated with a 23 valent PPS vaccine. The percentage of patients treated with methotrexate in the anti-TNF and no anti-TNF group was 65% and 76%, respectively. Antibodies against four of the vaccine antigens (PPS 6B, 9V, 19F and 23F) were measured before and 4 weeks after vaccination. The primary outcome was the response rate, defined as the percentage with a postvaccination titer 0.35 microg/ml in combination with at least a twofold increase in antibody titer. The protection rate was defined as a postvaccination titer > or = 0.35 microg/ml. RESULTS The use of methotrexate was the strongest predictor of impaired vaccination outcome. Anti-TNF caused an additional immunosuppressive effect in the presence of methotrexate, leading to the lowest response percentages in patients using the combination of these two drugs. The underlying disease, other immunosuppressives such as prednisone or type of anti-TNF agent used did not influence vaccination outcome. CONCLUSIONS Patients who were treated with the combination of methotrexate and anti-TNF demonstrated a significantly impaired immune response following pneumococcal polysaccharide vaccination as compared to patients treated with either methotrexate or anti-TNF only or immunosuppressives excluding these two compounds.