Pyrimethamine, a folate antagonist similar to methrotrexate without known hepatotoxcity in man, was administer orally, once a week, to seven patients with severe, long-standing psoriasis. Four patients obtained a good to excellent response; a fifth withdrew from the study early after a partial response; a sixth had minimal response to high doses, and the seventh was withdrawn due to a probable drug-induced hepatotoxic reaction. Hepatotoxic reaction was suspected in another patient with abnormal liver biopsy and experienced severe gastrointestinal toxic reactions and two developed significant thrombocytopenia, which resolved after oral treatment with folic acid or discontinuation of the drug. These did not recur at lower doses. Pyrimethamine appears to be effective in severe psoriasis, but offers no advantage, and several disadvantages over methotrexate. Pyrimethamine is probably hepatotoxic. It should be used with caution in patients with liver disease or impaired renal function; pretreatment liver biopsy is recommended.