Curcumin is a yellow-colored plant polyphenol with a long history of medicinal use in ayurvedic, Chinese and Japanese medicine. Studies have reported the cyclooxygenase COX-2-inhibitory activity of this polyphenol; however, none of the studies have established its antiinflammatory activity in the rat cotton pellet granuloma pouch model, which mimics subchronic inflammation in humans. The present study was conducted to evaluate the effect of curcumin in the cotton pellet granuloma pouch model. Furthermore, the interaction of curcumin with standard anti-inflammatory drugs at subeffective doses was studied to evaluate its potential role as adjuvant therapy. Administration of curcumin (240 mg/kg i.p.), aspirin (160 mg/kg i.p.) or rofecoxib (5 mg/kg i.p.) for 6 days in the cotton pellet granuloma pouch test exhibited significant anti-inflammatory activity, as demonstrated by a decrease in both dry and wet weights of the cotton pellet as compared to the control animals. Lower doses of curcumin (120 mg/kg i.p.), aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) were ineffective. However, the combination of a subeffective dose of curcumin (120 mg/kg i.p.) with submaximal doses of aspirin (80 mg/kg i.p.) or rofecoxib (2.5 mg/kg i.p.) produced a synergistic effect. Furthermore, there was marked increase in tumor necrosis factor-alpha (TNF-alpha) levels (estimated by enzyme-linked immunosorbent assay, ELISA) in the serum of the animals implanted with cotton pellets presenting marked inflammatory events. Daily administration of curcumin, aspirin or rofecoxib decreased the levels of TNF-alpha, further demonstrating anti-inflammatory activity. Curcumin in combination with aspirin or rofecoxib caused a further decrease in serum TNF-alpha levels. In conclusion, the results of the present study demonstrate an anti-inflammatory effect for curcumin in the cotton pellet granuloma pouch test, possibly acting through COX enzyme inhibition, and further inhibiting the generation of inflammatory mediators such as TNF-alpha. These results point toward the usefulness of curcumin as adjuvant drug therapy along with standard anti-inflammatory drugs.