Epidemiological data suggest an association between kidney stones and some features of metabolic syndrome such as an overweight condition, arterial hypertension or glucose intolerance. However, mechanisms remain to be elucidated. This study aimed to evaluate insulin resistance, as assessed by homeostasis model assessment (HOMA-IR), and urine composition analysis in patients affected by calcium nephrolithiasis. A cohort of 61 (38 male, 29-57 years of age) non-diabetic calcium stone formers was studied. Data about body mass index, arterial blood pressure, serum biochemistry including parathyroid hormone and calcitriol were recorded in all the patients; fasting glucose and insulin were determined to calculate HOMA-IR value and accordingly the patients were grouped into tertiles. Urine pH and urinary excretion of calcium, citrate, phosphate, oxalate, uric acid, urea and creatinine were measured on 24h urine samples. Patients of the highest HOMA-IR tertile showed lower urine citrate levels than patients of the lowest HOMA-IR tertile (475+/-243 vs. 630+/-187 mg/24h, p<0.05), whereas no difference was detected as far as urinary oxalate, calcium, uric acid, phosphate, and urine pH and urine volume output were concerned. HOMA-IR values were positively related to uric acid serum levels (r=0.31, p<0.05) and negatively to urinary citrate excretion (r=-0.26, p<0.05). Hypocitraturic patients showed higher levels of HOMA-IR than normocitraturic ones (3.03+/-0.92 vs. 2.25+/-1.19, p<0.05). This study shows that a higher level of insulin resistance is associated with lower urinary citrate excretion, and that hypocitraturic patients show a greater insulin resistance than normocitraturic calcium stone formers. This may be related to changes in citrate, Na(+)-K(+) and H(+) renal tubule transports, which have been described in insulin resistance. In conclusion, insulin resistance may contribute to an increased risk of calcium stone formation by lowering urinary citrate excretion. This finding suggests the need for a careful metabolic assessment in patients known to form calcium stones in order to ensure stone recurrence prevention and cardiovascular protection.