The effect of rofecoxib (Vioxx), a cyclooxygenase (COX)-2 inhibitor, on adipose tissue development was studied in a murine model of diet-induced obesity. Oral administration of Vioxx for six weeks (34 mg/kg/day) to C57Bl/6 mice kept on high-fat diet (n = 19) resulted in a significant reduction in total body weight (p < 0.01) and of subcutaneous (p < 0.05) and gonadal (p < 0.01) adipose tissue mass, as compared to placebo-treated animals (n = 21). There was no significant difference in food intake between both groups (2.8 +/- 0.09 vs. 3.0 +/- 0.10 g/day; p = 0.20). Administration of Vioxx resulted in reduced total cholesterol and high-density lipoprotein (HDL) cholesterol levels (p < 0.0001) and in enhanced levels of liver enzymes, as compared to place-bo. In the gonadal but not in the subcutaneous adipose tissue, adipocytes were smaller after Vioxx treatment (p < 0.05). The macrophage content was significantly lower in gonadal adipose tissues of Vioxx-treated mice (p < 0.05), but not in the subcutaneous adipose tissues. This was, however, not associated with differences in adipose tissue levels of the pro-inflammatory tumor necrosis factor (TNF)-alpha. Blood vessel size or density in either fat pad were not affected by Vioxx treatment. Thus, in a nutritionally induced murine obesity model, oral administration of Vioxx, as compared to placebo, resulted in reduced adipose tissue development, associated with lower feeding efficiency and smaller adipocytes.