The potent irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (MDL 28,842) was examined for its effect on the development and treatment of collagen-induced arthritis in mice. We have previously shown that MDL 28,842 inhibits T cell activation without affecting B cell activation. Animals were dosed with MDL 28,842 at 5, 2.5, or 1 mg/kg/day p.o. in water beginning 1 day before immunization with chick type II collagen (CII) and continuing through day 51 postimmunization. None of the animals treated with MDL 28,842 at 5 or 2.5 mg/kg/day developed arthritis compared with 87.5% of the controls. Animals treated with 1 mg/kg MDL 28,842 had a delay in the development of the disease and a decreased incidence of arthritis (55%) during the course of treatment. After the treatment was discontinued, 40% of the mice in the 5-mg/kg treatment group, 60% of the mice who had previously received 2.5 mg/kg MDL 28,842, and 27% of the mice in the 1-mg/kg treatment group remained free of any signs of arthritis. Treatment with MDL 28,842 also lowered serum anti-CII IgG levels. In addition, T cells taken from animals immunized with CII and treated with 2.5-mg/kg/day MDL 28,842 had a lower proliferative response to denatured CII in vitro than controls. Therapeutically, MDL 28,842 was administered to animals at 2.5 mg/kg/day p.o., beginning at the first clinical signs of arthritis and continuing for 4 wk. Over the course of treatment, there was significantly less clinical disease in animals given MDL 28,842. In addition, at the end of treatment, hind paws were removed from the animals and examined radiographically and histologically for joint pathology. Animals treated with MDL 28,842 had significantly fewer bone lesions than control animals. These results suggest that inhibitors of S-adenosyl-L-homocysteine hydrolase may be effective anti-arthritic agents.