Background: Rosiglitazone, a well known PPAR␥ agonist, stimulates adipocyte differentiation. Results: In C3H10T1/2 cells, rosiglitazone induces prolyl hydroxylase domain proteins 1, 2, and 3, resulting in the degradation of anti-adipogenic proteins such as GATA-3, KLF-2, and TAZ. Conclusion: Three isoforms of the prolyl hydroxylase domain protein play a key role in rosiglitazone-induced adipocyte differentiation. Significance: Novel mechanisms involved in rosiglitazone-induced adipogenesis would provide a better understanding of adipocyte biology.