Peroxisome proliferator-activated receptor γ (PPARγ) may serve as a useful target for drug development in non-diabetic diseases. However, some colorectal cancer cells are resistant to PPARγ agonists by mechanisms that are poorly understood. Here, we provide the first evidence that elevated PPARδ expression and/or activation of PPARδ antagonize the ability of PPARγ to induce colorectal carcinoma cell death. More importantly, the opposing effects of PPARδ and PPARγ in regulating programmed cell death are mediated by survivin and caspase-3. We found that activation of PPARγ results in decreased survivin expression and increased caspase-3 activity, whereas activation of PPARδ counteracts these effects. Our findings suggest that PPARδ and PPARγ coordinately regulate cancer cell fate by controlling the balance between the cell death and survival and demonstrate that inhibition of PPARδ can reprogram PPARγ ligand-resistant cells to respond to PPARγ agonists.