Single drug therapy is often not satisfactory in the treatment of chronic arthritis. The combination of second-line antirheumatic drugs is therefore increasingly employed. Various strategies of combining drugs can be used, starting with combinations or adding agents in case of insufficient effect of single therapy. Effective combinations have to be found empirically because lack of knowledge about pharmacodynamics and pharmacokinetics often hinders rational choices. Few controlled studies on combinations of second-line antirheumatic drugs exist, results suggesting very moderately increased efficacy and increased toxicity. Recently, results of combinations, mainly with methotrexate, have become available. Combining this agent with azathioprine did not offer advantages. Cyclosporin added to insufficiently effective methotrexate possibly has some value and antimalarials combined with methotrexate may be beneficial regarding effectivity and/or toxicity. Methotrexate added to insufficiently effective sulphasalazine seems to be better than methotrexate alone, although this combination when used from the start of the therapy was disappointing. Triple therapy of the latter combination together with hydroxychloroquine turned out to be superior to single methotrexate and to the combination of sulphasalazine and hydroxychloroquine. Surprisingly, the toxicity of these combinations was mainly comparable to single therapy. In conclusion, combinations of second-line antirheumatic drugs have a role, although not yet clearly defined, in the therapy of chronic arthritis.