The comparative effect of indomethacin and hydrocortisone on the resistance of mice or rats to various acute, subacute, and latent bacterial infections was investigated. Large daily doses of indomethacin and hydrocortisone administered to mice challenged with bacterial pathogens, including Klebsiella pneumoniae AD, Salmonella schottmuelleri 3010, Staphylococcus aureus (Smith), Streptococcus pyogenes C203, Salmonella pullorum #2, Proteus vulgaris 1810, and Pseudomonas aeruginosa 2616, revealed that in essentially all of these acute infections, the mortality of the infected mice treated with indomethacin was essentially identical to that found in the infected controls. In contrast, hydrocortisone often lowered the resistance of mice to these acute infections. In a more chronic bacterial infection due to Corynebacterium kutscheri, hydrocortisone produced striking deleterious effects on resistance, whereas indomethacin administration in doses approaching the maximal tolerated level caused no observable adverse effects on host resistance. Indomethacin fed continuously to rats for 80 days, at maximal tolerated levels, caused no observable adverse effects on the host-parasite relationship of rats which were shown to harbor various latent infections. Hydrocortisone administration, however, lowered the resistance of rats as evidenced by increased mortality related directly to extensive bacterial infection. Insofar as infection is concerned, indomethacin behaved like other nonsteroid anti-inflammatory agents such as aspirin and phenylbutazone.