Seventy-two patients with rheumatoid arthritis had been treated with pulse weekly oral methotrexate with a mean followup of one year. Minor side effects (oral ulcers, transient elevation of liver enzymes, nausea, vomiting) were present in 46 patients (63.8%), whereas major side effects (severe infection, cytopenia, respiratory failure, seizures, gastrointestinal bleeding) were present in 7 (9.7%), 2 of whom died. Patients with major side effects had shorter disease duration and increased frequency of extraarticular manifestations as compared to those with no side effects. No association between a particular clinical or genetic variable and occurrence of side effects to methotrexate was found.