It is well known that metabolic syndrome (MS) is a risk factor for proteinuria and chronic kidney disease. Losartan (angiotensin II receptor blocker, ARB) and pioglitazone (peroxisome proliferator-activated receptor-γ, PPARγ agonist) have been shown to confer renoprotection. However, to date, whether or not an ARB and a PPARγ agonist have synergistic renoprotective effects remains controversial. Thus, the present study was designed to evaluate a combined treatment with losartan and pioglitazone in Sprague-Dawley rats fed with a high-fat, high-salt (HFS) diet and 20% sucrose solution for 16 weeks, an animal model of MS accompanying with renal lesions. Losartan, pioglitazone, and their combination were orally administered in the MS rats from 8 weeks to the end of this study. At 16 weeks, the MS rats showed the elevation in systolic blood pressure (SBP), urinary albumin excretion (UAE), and glomerulosclerosis (GS) score, but creatinine clearance, urinary protein excretion, and score of tubulointerstitial damage were not affected. Renal vascular endothelial growth factor (VEGF) protein level, mRNA and protein expression, which were respectively measured by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analysis, were obviously decreased in the MS rats. Treatment with the combination of losartan and pioglitazone provided synergistic effects in reducing the SBP, UAE, and GS score when compared with monotherapy. These effects were not associated with ameliorated the downregulation of renal VEGF expression. Our data suggest that combined treatment with losartan and pioglitazone may offer additional advantages in treating MS nephropathy.