We report unexpected anti-inflammatory properties for naked, unmodified poly(amidoamine) (PAMAM) dendrimers bearing simple surface functionality (e.g., -NH2, -OH, etc.). This property was discovered serendipitously while studying the drug delivery features of PAMAM dendrimer-indomethacin complexes. Activity was quantitated by using three independently recognized in vivo anti-inflammatory assay methods, namely, (1) the carrageenan-induced paw edema model (acute activity), (2) the cotton pellet test, and (3) the adjuvant-induced arthritis assay in rats (chronic activities). Those dendrimers bearing amine or hydroxyl surface groups exhibited significant anti-inflammatory activity in the carrageenan-induced paw edema model. For example, core: 1,2-diaminoethane]; (G = 4.0); (dendri-poly(amidoamine)-(NH2)(64)} (i.e., G4-NH2) exhibited a mean percent inhibition of 35.50 +/- 1.6% 3 h after administration and core: 1,2-diaminoethane] (G = 4.0); (dendri-poly(amidoamine)-(OH)64} (i.e., G4-OH) gave a mean percent inhibition of 31.22 +/- 1.58% 3 h after administration. On the other hand, core: 1,2-diaminoethane] (G = 4.5); (dendri-poly(amidoamine)-(CO2H)(128)} (i.e., G4.5-CO2H) exhibited mild anti-inflammatory activity with a mean percent inhibition of 14.00 +/-2.5% 3 h after administration. Unexpectedly, G4-NH2 showed significantly higher activity compared to naked indomethacin (i.e., 50 +/- 3.1 % vs 22 +/- 1.2%) using the cotton pellet granuloma model. Similarly, in the adjuvant-induced arthritis model, G4-NH2 compared to naked indomethacin gave a mean percent inhibition of 30 +/- 1.9% versus 11 +/- 0.9% 14 days after administration.