Elevated serum levels of osteopontin have been associated with cardiovascular disease, diabetic nephropathy, and autoimmune disease activity. Aim of the study was to investigate the relationship between osteopontin serum levels and renal damage in a population of patients with systemic lupus erythematosus (SLE). Osteopontin serum levels were analyzed in 101 SLE patients and compared to those of 115 healthy controls. Associations between osteopontin levels and renal involvement, disease activity and damage index, biochemical parameters, and therapy were assessed. Overall osteopontin serum levels were higher in SLE patients (median, 17.93 ng/mL; interquartile range, 8.13-35.07 ng/mL) than in healthy controls (median, 5.62 ng/mL; interquartile range, 2.61-13.83 ng/mL). Univariate logistic analysis among cases showed that high osteopontin levels (higher vs medium-lower tertile) were associated with renal involvement (p = 0.012), renal function (p = 0.007), proteinuria (p = 0.011), anemia (p < 0.001), and SLICC/ACR Damage Index (p < 0.001). Multivariate analysis showed an independent association between high osteopontin serum levels (higher vs medium-lower tertile) and chronic kidney disease (OR = 4.89; 95 % CI, 1.24-19.24; p = 0.008), proteinuria (OR = 4.56; 95 % CI, 1.15-18.04; p = 0.027), anemia (OR = 4.66; 95 % CI, 1.25-17.43; p = 0.008), and use of renin-angiontensin system antagonists (OR = 0.234; 95 % CI, 0.06-0.98; p = 0.047). This study shows that elevated osteopontin serum levels significantly correlate with renal involvement and anemia in SLE. Moreover, it suggests that renin-angiontensin system antagonists decrease osteopontin levels-this effect is consistent with the inhibitory effect of these drugs on osteopontin renal expression, detected in animal models by other authors, and may provide a new rationale for their employment.