The purpose of the present study was to evaluate the toxicity and tolerability of methotrexate (MTX)/gold (G; group 1) combination therapy as compared to other MTX combinations [MTX with hydroxychloroquine (HCQ; group 2), MTX with sulphasalazine (SASP; group 3) and MTX with minocycline (MNC; group 4)]. The hospital records of 127 consecutive rheumatoid arthritis (RA) patients who were treated with these combinations during a period of 24 months were retrospectively reviewed. The toxicity and tolerability of the MTX/G combination was compared to the other dual MTX combinations and also to MTX alone using data previously reported by us on 126 RA patients treated with single MTX therapy. The mean exposure time to treatment was 16 months in group 1 and 13 months in the other dual MTX combinations. During the period of follow-up, the combination was stopped in 22 out of 42 patients in group 1 (52%) in comparison with 54 patients out of 86 patients (63%) in the other dual regimen groups. The discontinuation rate was highest in group 4 (due to side effects and lack of compliance) and this was statistically significant in comparison with group 1. The proportion of adverse events was lowest in group 1 (14%) and highest in groups 3 and 4 (25%). Side effects were reversible and comparable with those of MTX alone (23%). No fatal or life-threatening side effects were recorded during any of these MTX combination therapies. We concluded that the combinations of MTX with G, HCQ, SASP and MNC in RA were relatively well tolerated. No increase in toxicity compared with MTX alone was observed. The lowest rate of side effects was noted in group 1, while group 4 presented the highest discontinuation rate.