The emergence of kidney disease as an important comorbidity among human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) has emphasized the critical importance of early identification of patients at risk for kidney disease. Use of urine as a diagnostic medium may allow the noninvasive detection of incipient nephropathy in these patients. Here, we conducted cross-sectional and 1-year prospective studies of 424 HIV-infected patients on HAART without proteinuria or significant impairment of glomerular function. N-acetyl-β-D-glucosaminidase, γ-glutamyl transpeptidase, β(2)-microglobulin and α(1)-microglobulin were measured as indices of tubular damage, which was diagnosed when urinary concentrations of at least three tubular biomarkers exceeded the reference range. Risk factors associated with tubular damage were examined using multivariate logistic regression analysis. Tubular damage was identified in 107 patients (25%), who were characterized by advanced age odds ratio (OR), 1.04; 95% confidence interval (CI), 1.01-1.07, high C-reactive protein (OR, 1.96; 95% CI, 1.26-3.14) and coexisting diabetes mellitus (OR, 3.97; 95% CI, 1.44-12.2). The use of tenofovir, the most likely tubulotoxic agent, was not statistically involved in this subclinical tubular damage. The 1-year follow-up study showed that a decrease in estimated glomerular filtration rate (eGFR) and incidence of proteinuria during the period were significantly higher in patients with than without tubular damage. A quarter of HIV-infected patients receiving HAART had subclinical tubular damage, which was associated with a near-term decline in eGFR and higher incidence of proteinuria. Periodic monitoring of urinary biomarkers might facilitate the early identification of HAART patients predisposed to significant kidney disease.