The mechanism of amphotericin B (AmB) nephrotoxicity may be related to changes in vascular flow within the kidney, resulting in significant decreases in glomerular filtration rate and tubular integrity. The toxic and antifungal effects of AmB with and without the vascular decongestants pentoxifylline (PTX) and a methylxanthine analog, HWA-138, were compared in the murine model of candidiasis. At 48 h after inoculation with Candida albicans, half of the rats received a single intravenous 0.8 mg/kg dose of AmB whereas the others were administered sterile water. After 1 h, rats were randomized to receive three doses of 45 mg/kg PTX intraperitoneally, 5 mg/kg HWA-138 intravenously, or saline every 12 h. Renal function and Candida cell counts were estimated 24 h after AmB administration. Mean inulin clearances were significantly greater in rats coadministered AmB and PTX or HWA-138 than in AmB controls. Candida counts in kidneys of rats administered HWA-138 were similar independent of AmB therapy and markedly reduced compared with other groups. Whereas both vascular decongestants prevented drug-associated renal toxicity, the coadministration of AmB with HWA-138 resulted in a profound antifungal effect.