The peroxisome proliferator-activated receptor γ (PPARγ) mediates the activity of the insulin-sensitizing thiazolidinediones and plays an important role in adipocyte differentiation and fat accretion. The analysis of PPARγ functions in mature adipocytes is precluded by lethality of PPARγ^–/– fetuses and tetraploid-rescued pups. Therefore we have selectively ablated PPARγ in adipocytes of adult mice by using the tamoxifen-dependent Cre-ER^T2 recombination system. We show that mature PPARγ-null white and brown adipocytes die within a few days and are replaced by newly formed PPARγ-positive adipocytes, demonstrating that PPARγ is essential for the in vivo survival of mature adipocytes, in addition to its well established requirement for their differentiation. Our data suggest that potent PPARγ antagonists could be used to acutely reduce obesity.