Background The prevalence and factors associated with an increased risk of renal dysfunction in HIV‐infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings. Methods Patients in the ICONA Foundation cohort with at least two creatinine values available while still ART‐naïve were enrolled in the study. A logistic regression analysis was performed to identify predictors of an estimated glomerular filtration rate (eGFR)<90 mL/min/1.73 m2 at baseline. The incidence and predictors of a >20% reduction in eGFR from pre‐combination ART (cART) levels (or a decrease from ≥90 to <90 mL/min/1.73 m2) were evaluated by Poisson regression. Results A total of 1505 patients were included in the study; 363 (24%) had eGFR<90 mL/min/1.73 m2 at baseline. Older patients odds ratio (OR) 1.58 per 10 years older; P<0.00001, female patients (OR 2.41 vs. male patients; P<0.00001), those who had diabetes and/or hypertension (OR 2.36 vs. neither; P<0.03) and patients with higher baseline CD4 count (OR 1.06 per 100 cells/μL higher; P<0.03) showed a greater risk of eGFR<90 mL/min/1.73 m2. Ninety‐six patients experienced an eGFR decrease of >20% from pre‐cART levels (6.8 per 100 person‐years). Older age relative risk (RR) 1.41 per 10 years older; P=0.005, female gender (RR 2.25 vs. male; P=0.003) and current exposure to didanosine (ddI), tenofovir and protease inhibitors were the major determinants. Conclusions We observed a relatively high rate of mild renal dysfunction in the absence of ART. In addition to traditional risk factors such as older age and diabetes/hypertension, female gender and current use of ddI, tenofovir and protease inhibitors were associated with a greater risk of decreased renal function as measured by eGFR.