BACKGROUND. Despite extensive investigation, the role of MDR of human cancer remains unclear. Canine lymphoma is a spontaneously arising correlate of human non-Hodgkin's lymphoma that may complement other in vivo models for investigation of issues related to MDR. METHODS. Immunoreactivity of primary antibodies to the human MDRl gene product, p-glycoprotein 170 (Pgp), were determined in both a retrospective (n = 76) and prospective (n = 15) survey of canine lymphoma. Known prognostic factors and response to chemotherapy were correlated with categorical-designations of Pgp expression. RESULTS. When combined, 61 of 91 samples (67%) were negative for Pgp, 16 of 91 (17.5%) had strong Pgp immunoreactivity in >50% of the malignant population and 14 of 91 (15.5%) had Pgp reactivity in 10-50% of cells. Pgp expression was greater after relapse compared with pretreatment samples IC494 83% vs. 25%; P = 0.012 and C219 73% vs. 27%; P = 0.041. Pretreatment Pgp expression was an independent negative predictor of overall suMval (median = 225d vs. 367d; P = 0.02). CONCLUSIONS. Pgp expression in spontaneous canine lymphoma is similar to that reported in human non-Hodgkin's lymphoma. Use of this model may expedite investigation of novel strategies for MDR prevention or modulation.