In order to better characterize the pathogenesis of alpha 2u-globulin (alpha 2uG) nephropathy, cell proliferation was quantitated within the three proximal tubule segments of the kidney (P1, P2, and P3) and proximal tubule segments affected by chronic progressive nephrosis (CPN) in male and female F344 rats exposed to 10, 70, or 300 ppm unleaded gasoline (UG) or 50 ppm 2,2,4-trimethylpentane (TMP) from 3 to 50 weeks. The P2 segment of male rats exposed to UG or TMP responded with dose-related increases in cell turnover (up to 11-fold) that persisted during chronic exposure. This proliferative response closely paralleled the extent and severity of immunohistochemically detectable alpha 2uG in the P2 segment. Neither alpha 2uG nor cytotoxicity was evident in cells of the P1 or P3 segment; however, cell proliferation was increased (up to 8-fold) for up to 22 weeks of exposure in the P3 segment. Increased numbers of proximal tubules affected by CPN were found in males exposed to UG or TMP for 22 or 48 weeks, compared to controls. These lesions contained epithelial cells that were highly proliferative. Control or treated female rats exhibited neither alpha 2uG nephropathy nor increases in P2 or P3 cell turnover, and the extent of CPN was greatly reduced as compared to male rats. The results of this and related studies suggest that chronic cell proliferation associated with alpha 2uG nephropathy and CPN in male rats exposed to UG or isoparaffinic components of UG, such as TMP, may be responsible for the sex- and species-specific nephrocarcinogenic effects of UG.