Renal damage was assessed by histopathology and urinalysis in male Wistar rats treated with either hexachloro-1:3-butadiene (HCBD; a single 170-mg/kg ip dose that caused proximal tubule necrosis), adriamycin (ADR; a single 5-mg/kg ip dose that caused minimal glomerular changes up to 35 days), or HCBD given 2 wk after ADR and compared with age-matched control rats for 21 days. Urinalysis values in ADR-treated rats showed minimal renal changes. HCBD significantly elevated urine volume (10-fold), protein (5-fold), glucose (175-fold), and brush border enzymes (10-600-fold), indicating severe proximal tubular damage, but most parameters returned to pretreatment levels 6 days after treatment. In ADR-pretreated rats subsequently given HCBD, both the urinary alkaline phosphatase and the ratio of kidney: body weight were significantly higher for longer periods. Histopathology demonstrated that the HCBD-induced proximal tubular lesion was confined to the outer stripe of the outer medulla. Advanced regeneration and repair was evident 21 days after HCBD treatment. In the ADR-pretreated rats the HCBD-induced lesion was more severe and affected the entire cortex and was characterized by marked tubular epithelial calcification, with little evidence of repair and tubular restitution 21 days after treatment. Enzyme histochemistry showed gamma-glutamyltranspeptidase localized to the proximal tubules. After HCBD treatment the enzyme staining was lost and subsequently returned in parallel with histological recovery up to 21 days. The distribution and intensity of gamma-glutamyltranspeptidase was unchanged in ADR-treated rats. The distribution and intensity of gamma-glutamyltranspeptidase in kidneys of ADR-pretreated rats given HCBD had not returned to normal by day 21. The results of this study indicate that pretreatment with ADR increases HCBD-induced nephrotoxic damage and decreases renal cortical repair capacity.