The effects of daily subcutaneous administration of prostaglandin E1 (PGE1), theophylline, and of both drugs together were studied on the Freund's adjuvant-induced inflammatory and arthritic syndrome in rats. In the doses used, neither drug affected the acute inflammatory response in the adjuvant-treated paw, but together they caused marked inhibition. Chronic inflammation in the contralateral (nontreated) hind paws was slightly inhibited by each drug and combined treatment resulted in marked inhibition. The drugs also counteracted splenomegaly in adjuvant-diseased rats and their effects on spleen weight paralleled the inhibition of chronic inflammation. Arthritic lesions, as judged by x-rays of tibiotarsal joint destruction in the nontreated paws, were partially prevented by PGE1 alone, but not by theophylline. The combined treatment entirely prevented these joint lesions. PGE1 did not cause an increase in adrenal weight, but enhanced the effect of theophylline on adrenal weight. Only PGE1 improved gait in arthritic rats, simultaneous theophylline treatement having little additional effect. Other workers have found the PGE1 increases intracellular cAMP and that this effect is enhanced by the phosphodiesterase inhibitor, theophylline. We propose that the anti-inflammatory and anti-arthritic effects of combined drug treatment involve cAMP changes in phagocytic cells at the site of tissue injury and in systemic lymphocytes.