Astaxanthin (ASX), an oxygenated carotenoid (xanthophyll), has previously been shown to exert ameliorative effects on obesity and insulin resistance, but the underlying mechanisms were not clearly elucidated. In the present study, we investigated whether ASX serves as a novel selective peroxisome proliferator-activated receptor (PPAR) γ modulator. Analyses of PPARγ binding by CoA-BAP assays revealed that ASX bound to PPARγ in a dose-dependent manner. However, ASX was unable to activate transcription in PPARγ reporter assays, although it antagonized transcriptional activation by the PPARγ agonist rosiglitazone (RGZ). When the molecular interactions between PPARγ and three coactivators were examined, ASX increased the interactions of PPARγ with transcriptional intermediary factor 2 (TIF2) and steroid receptor coactivator-1 (SRC-1), but not cAMP responsive element-binding protein (CREB)-binding protein (CBP). In addition, ASX effectively blocked the increase in CBP recruitment to PPARγ mediated by RGZ. ASX alone did not stimulate 3T3-L1 cell differentiation, although it antagonized 3T3-L1 cell differentiation and lipid accumulation induced by RGZ, similar to the PPARγ antagonist GW9662. When the effects of cotreatment of 3T3-L1 cells with ASX and RGZ were determined based on the mRNA levels of PPARγ target genes, ASX effectively reduced the mRNA levels of aP2 and lipoprotein lipase, but not CD36. Intriguingly, ASX was capable of inducing PPARγ target genes such as liver X receptor, CD36 and ABCA1 in thioglycollate-elicited peritoneal macrophages. Collectively, the present findings indicate that ASX is a novel selective PPARγ modulator that acts as an antagonist or agonist depending on the cell context.