Purpose: To determine (1) whether nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs) are differentially expressed in normal and in cancerous human prostate tissues and (2) whether oral fenretinide therapy impacts the expression of these receptors in prostate cancer. Patients and Methods: In situ hybridization with antisense riboprobes was used to probe for RAR and RXR transcripts in prostate tissues in a two-phased study: (1) expression of retinoid receptors in eight normal prostates was compared with their expression in 10 randomly picked radical prostatectomy specimens (group A); (2) expression of retinoid receptors was determined in 22 radical prostatectomy specimens from participants in a clinical study (group B). Twelve patients received oral fenretinide 200 mg/d, and 10 received placebo pills for 28 days before surgery. Results: RARα, RARγ, RXRα, and RXRγ, mRNAs were detected in most normal and cancerous prostates. In group A, RARβ mRNA was expressed in only four of 10 malignant prostates but was present in seven of eight benign prostates (P = .05). RXRβ mRNA was expressed in four of eight benign prostates and in zero of 10 malignant prostates (P = .023). In group B prostates, RARβ and RXRβ mRNAs were markedly reduced in all cancers and in the adjacent, nonmalignant tissue. There were no differences between receptor expression in the fenretinide-treated group and the placebo group. Conclusion: RARβ and RXRβ mRNAs are selectively lost in both prostate cancer and adjacent morphologically normal prostatic tissue, supporting the concept of a field of carcinogenesis. One month of oral fenretinide (200 mg/d) did not influence the expression of retinoid receptors in prostate cancer.