Purpose: To investigate the expression significance of PPAR b/d in relation to radiotherapy (RT), clinicopathologic, and prognostic variables of rectal cancer patients.Experimental Design: We included 141 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. Tissue microarray samples from the excised rectal cancers and the adjacent or distant normal mucosa and lymph node metastases were stained with PPAR d antibody. Survival probability was computed by the Kaplan-Meier method and Cox regression model. The proliferation of colon cancer cell lines KM12C, KM12SM, and KM12L4a was assayed after PPAR d knockdown.Results: PPAR d was increased from adjacent or distant normal mucosa to primary cancers, whereas it decreased from primary cancers to lymph node metastases. After RT, PPAR d was increased in normal mucosa, whereas it decreased in primary cancers and lymph node metastases. In primary cancers, the high expression of PPAR d was related to higher frequency of stage I cases, lower lymph node metastasis rate, and low expression of Ki-67 in the unirradiated cases, and related to favorable survival in the cases either with or without RT. The proliferation of the KM12C, KM12SM, or KM12L4a cells was significantly accelerated after PPAR d knockdown.Conclusions: RT decreases the PPAR d expression in primary rectal cancers and lymph node metastases. PPAR d is related to the early development of rectal cancer and inhibits the proliferation of colorectal cancer cells. Increase of PPAR d predicts favorable survival in the rectal cancer patients either with or without preoperative RT.