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Context: Nonsteroidal antiinflammatory drugs (NSAIDS) are mainstay of therapy in various inflammatory conditions. Its long-term use is associated with acid peptic diseases requiring prophylaxis with antiulcer drugs. Thus the question arises whether inhibition of gastric acid secretion affects the bioavailability of NSAIDS. Thus prescribing NSAIDS together with H2 blockers seems to be a safe strategy but the combination becomes less effective for its primary intention. Aims: To evaluate the effect of combination therapy on efficacy of NSAIDs in terms of analgesic, antiinflammatory and antipyretic activity. Settings and Design: Experimental study in albino rats. Materials and Methods: Evaluation of analgesic activity was done by acetic acid writhing model, antiinflammatory activity was assessed using carrageenin-induced paw edema and for antipyretic activity yeast was used (n = 6). Gastric juice pH was analyzed. Statistical Analysis: Comparison between different groups was done by one-way analysis of variance (ANOVA) followed by Tukey's test using Graph pad prism software version 5.01. The analgesic, antiinflammatory, and antipyretic activity was significantly reduced when aspirin, diclofenac and piroxicam were combined with famotidine. There was a pH rise in H2 blockers pretreated groups, which was more with famotidine as compared with ranitidine pretreated group. Conclusions: Prescribing NSAIDs and H2 blockers together seems to be safe strategy but the drug combination becomes less effective for its primary intention of reducing pain, fever, and inflammation. [ABSTRACT FROM AUTHOR]