OBJECTIVE: To explore whether the mechanism of action of 4-hydroxyphenylretinamide (4-HPR, fenretidine), a synthetic retinoid, involves the functional activation of the nuclear hormone receptor class known as PPARs (peroxisome proliferator-activated receptors). Also, to examine whether anti-proliferative effects of this agent in head and neck cancer cells occur at biologically relevant concentrations. STUDY DESIGN/METHODS: CA 9-22, NA, and UM SCC 11B cells were treated with 4-HPR during their log phase growth and functional activation of PPAR γ was evaluated by plate luminometry. Cellular proliferation was analyzed by standard MTT cell proliferation assays and cell counting. Student's t tests were performed for all experiments. RESULTS: Significant dose-dependent increases in PPAR γ activation occurred in response to 4-HPR treatment. Proliferation was significantly inhibited by 4-HPR in a dose-dependent manner as judged by MTT and cell counting assays. These effects occurred at equimolar concentrations in both types of experiments within a range of clinically achievable doses (1-4 μM) of 4-HPR. CONCLUSIONS: 4-HPR can functionally activate PPAR γ at clinically achievable doses. Decreased cancer cell proliferation secondary to PPAR γ activation has been observed in other malignancies as well as upper aerodigestive cancer. PPAR γ activation by 4-HPR represents another potential anti-cancer mechanism of action for this drug. CLINICAL SIGNIFICANCE: PPAR γ activation represents a novel target for anti-cancer therapy for head and neck cancer and the current level of clinical toxicity of 4-HPR would be judged acceptable to utilize this agent alone or in combination chemotherapy.