The long term effects of indomethacin, cyclosporin, cyclophosphamide, and placebo on collagen-induced arthritis in mice were tested under two different treatment protocols. A prophylactic experiment examined the effects of the daily drug administration for 180 days beginning one day before the first collagen injection. Under this dosage schedule, cyclophosphamide and cyclosporin decreased the severity of arthritis, while indomethacin did not. A therapeutic protocol examined the effects of these same drugs when daily administration was delayed until the animals had active disease at 78 days after the first collagen injection. Under this protocol, all three drugs reduced the progression of disease. In both protocols, the most significant suppression of arthritis was seen in animals receiving cyclophosphamide which was associated with a decrease in anti-collagen antibody levels. Collagen-induced arthritis in mice should be further investigated as a model to study the long term effects of "slow-acting" anti-rheumatic drugs.