(NZB x NZW)F1 mice initiated on fat restriction at weanling were significantly protected from the development of immune complex glomerulonephritis. Whereas the mice on high-fat intake demonstrated immune depositions both in capillary walls and mesangial areas in a diffuse granular pattern, those on a low-fat diet with caloric content similar to the high-fat diets exhibited mesangial confinement of the depositions of immunoglobulins, complement, and retroviral gp70. In association with these divergent patterns of immune deposition, the mice on high-fat diets had evidence of extensive diffuse cellular proliferation, wire loop lesion, and sclerosis in the glomeruli. In contrast, most of the mice on the low-fat diet showed only mesangial cell and matrix proliferations. In addition, the group of mice fed high saturated fat showed more severe glomerular pathology as compared to those fed high unsaturated fat. Paradoxically, levels of circulating immune complexes (as measured by the polyethylene glycol precipitation technique) in the high saturated fat group were low and did not correlate with the findings by light and immunofluorescence microscopy. These findings suggest that dietary fat restriction can serve as either a prophylactic or effective therapeutic approach to murine lupus nephritis.