Methotrexate is one of the most effective and widely used medications in the treatment of rheumatoid arthritis. One poorly understood side effect of methotrexate is increased rheumatoid nodule formation, a phenomenon which has been reported to occur in some patients despite suppression of synovial inflammation. Using an in vitro model of nodulosis, induction of monocyte differentiation into multinucleated giant cells, we previously found that methotrexate promotes this inflammatory response by a mechanism dependent on adenosine A1 receptor stimulation. In the current study, we tested the effects of an A1 signal inhibitor, the commonly available anti-inflammatory medication colchicine, and found that it markedly inhibited nodulosis in vitro as well as in seven of fourteen patients in a clinical series.