OBJECTIVE: Renal disease is an increasingly common manifestation among HIV-positive persons, particularly during late stages of HIV disease. We performed a cohort-based, nested case-control study to examine the role of several factors in developing HIV-related chronic renal disease, including HIV viral load and CD4+ cell count. DESIGN: Incident cases of chronic renal disease were identified from a cohort of 6361 prospectively followed HIV-1 positive persons. Controls were selected using incidence density sampling and matched 4:1 on age, race/ethnicity, and gender. METHODS: Odds ratios (OR) and 95% confidence intervals (CI) were obtained using conditional logistic regression. RESULTS: One hundred and eight cases of chronic renal disease were identified; 80 (74.1%) were eligible for the current analysis. Nadir CD4+ cell count < 200 x 10(6) cells/l (OR = 4.3; 95% CI, 2.1-8.7), highly active antiretroviral therapy (HAART) use for 56 days or more (OR = 0.5; 95% CI, 0.3-1.0), and hypertension [treated with angiotensin-converting enzyme (ACE) inhibitors: OR = 4.6; 95% CI, 1.8-11.6; treated with non-ACE inhibitors: OR = 2.5; 95% CI, 1.0-6.2; not treated: OR = 4.2; 95% CI, 0.8-21.6] were associated with disease. HAART use for 56 days or more modified the associations for nadir CD4+ cell count and hypertension. CONCLUSIONS: Our findings suggest that advanced HIV-disease, as indicated by low CD4+ cell count, is associated with subsequently developing chronic renal disease and treatment with HAART may reduce the risk of developing chronic renal disease.