We studied the interaction of S-methylisothiourea (a selective inducible nitric oxide synthase inhibitor) with rofecoxib (selective cyclooxygenase-2 inhibitor) and mefenamic acid (non-selective cyclooxygenase inhibitor) in Brewer's yeast-induced pyrexia in mice by isobolographic analysis. Each drug was effective in reducing pyrexia when used alone. Log-dose-response curves of all the three drugs did not show any significant departure from parallelism indicating thereby, a common mode of antipyretic action. However, rofecoxib exhibited significantly higher potency than S-methylisothiourea. Isobolographic analysis of combination of S-methylisothiourea with rofecoxib and mefenamic acid revealed additive interaction. Experimental ED(50) of the combinations was not significantly different from theoretical additive ED(50) of the corresponding drug combination, that substantiated the additive nature of interaction between inducible nitric oxide synthase and cyclooxygenase in Brewer's yeast-induced fever in mice. Results suggest involvement of a mediator that is subservient to both inducible nitric oxide synthase and cyclooxygenase-2 enzyme activities. For further investigation, peroxynitrite ion may be considered to be the putative mediator.