Oxidative stress and inflammation have been implicated in obesity and insulin resistance. As a selenium transporter, ubiquitously expressed selenoprotein P (SePP1) has been known to play a role in the regulation of antioxidant enzyme activity. However, its adipose expression and regulation in obesity and insulin resistance has not been explored. Herein, we investigate the adipose expression of SePP1 in obesity and insulin resistance and its regulation in response to oxidative and inflammatory molecules in 3T3L1 adipocytes. We showed that the expression of Sepp1 gene was significantly reduced in both adipose tissue and liver of ob/ob mice and high fat diet‐induced obese mice. Moreover, the expression of Sepp1 gene was decreased in isolated adipose cells from Zucker obese rats and insulin‐resistant patients. Our studies in 3T3‐L1 adipocytes demonstrated that both undifferentiated 3T3‐L1 fibroblasts and differentiated adipocytes were capable of synthesizing Sepp1 protein in the glycosylated and non‐glycosylated forms. The treatment of either TNFα or hydrogen peroxide for 24 hours caused a significant reduction in SePP1 gene expression in a dose‐dependent manner in 3T3L1 adipocytes. Thus, we demonstrate that the adipose expression of SePP1 is decreased in obesity and down‐regulated by oxidative and inflammatory molecules, suggesting a possible role of Sepp1 in oxidative stress/inflammation‐associated insulin resistance in adipocytes.