Adriamycin (ADR) administration in susceptible rodents such as BALB/c mouse strain produces injury to the glomerulus mimicking human focal glomerular sclerosis (FSGS). The goal of the present study was to use this model to investigate antiproteinuric action of nitro-oleic acid (OA-NO₂), a nitric oxide-derived endogenous lipid product, which has exhibited multiple attractive signaling properties particularly in the kidney. BABL/c mice were pretreated for 2 days with OA-NO₂ at 5 mg/kg/day via osmotic mini-pump, followed by a single injection of vehicle or adriamycin (10 mg/kg) via tail vein. Albuminuria and renal function were analyzed at 1 wk post ADR treatment. ADR mice developed prominent albuminuria, hypoalbuminemia, hyperlipidemia and severe ascites. In contrast, the symptoms of nephrotic syndrome were greatly improved by OA-NO₂ treatment. In parallel, plasma creatinine and plasma urea nitrogen were elevated in ADR group and the severity was less in the ADR+OA-NO₂ group. OA-NO₂ attenuates ADR-induced glomerulosclerosis, podocyte loss, and tubulointerstitial fibrosis. Indices of oxidative stress including plasma and urinary TBARS and renal expression of NAD(P)H oxidase p47^phox and gp91^phox, and inflammation including renal expression of TNF-α, IL-1β and MCP-1 in response to ADR were all similarly suppressed. Together, these findings suggest that OA-NO₂ exerts renoprotective action against ADR nephropathy likely via its anti-inflammatory and anti-oxidant properties.