The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxifylline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p < .01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/cytotoxic T-cells (0X8+), in kidneys of rats given either treatment compared with PAN con-trol rats. In summary, both pentoxifylline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role of pentoxifylline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.