The purpose of the paper was to determine whether two clinically active antirheumatic compounds, cyclosporin-A (CS-A) and methotrexate (MTX) were efficacious in the treatment of adjuvant arthritis (AA) in rats, as measured by reduction of paw inflammation, lymphocyte activating factor (LAF) activity and the acute phase response. Parameters of the acute phase response consisted of plasma fibronectin (Fn), C-reactive protein (CRP), albumin and iron. Rats injected with Freund's complete adjuvant on day 1, developed systemic arthritis, which was quantitated by measuring non-injected paw swelling on day 17. When compared to normal animals, AA rats had significantly (P less than or equal to 0.01) increased: (1) splenic LAF activity (100% increase), (2) plasma Fn (58%), and (3) CRP (122%), as well as abnormally reduced levels of: (1) plasma albumin (53% reduction), and (2) iron (54%). Orally dosing AA rats from days 3 to 17 with the immunoregulatory drugs, CS-A (3 and 5 mg/kg) or MTX (0.5 and 1 mg/kg), significantly (P less than or equal to 0.01) reduced paw inflammation (100% reduction), increased final body wt 40-50 g over arthritic controls and decreased LAF activity from splenic leukocytes. The acute phase response, often associated with a high degree of LAF activity, was significantly (P less than or equal to 0.01) decreased by dosing with CS-A (3 and 5 mg/kg) and MTX (0.5 and 1 mg/kg). The inhibition of the acute phase response was measured by reduction of high plasma Fn levels (42-79% decrease) and CRP levels (57-100% decrease) as well as elevation of subnormal levels of plasma albumin (57-101% increase) and iron (40-114% increase). Dosing with the nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (50 and 100 mg/kg) or phenylbutazone (10 and 30 mg/kg), significantly inhibited paw inflammation (29-85%), but did not decrease the high rate of splenic LAF activity, nor did aspirin (55, 100 and 200 mg/kg) or phenylbutazone (1, 10 and 30 mg/kg) alter the acute phase response in AA rats, as measured by levels of plasma Fn, CRP, albumin and iron. Since CS-A and MTX have been reported to be effective in the treatment of RA, their activity in the LAF, Fn, CRP, albumin and iron assays of the AA rat suggests that these immunological and serological parameters may be useful in identifying potential antirheumatic drugs and distinguishing them from standard NSAIDs.