Aims: While angiotensin-converting enzyme inhibitors and zidovudine may improve the course of the most common HIV-related renal disease, HIV-associated nephropathy (HIVAN), the effect of antiretroviral combination therapy on this and other HIV-related renal diseases has not been assessed. This study describes the clinical course of HIV-related renal diseases and the effect of protease inhibitors on their progression. Methods: This retrospective cohort study reviews the clinical course of 19 patients with a clinical or biopsy-proven diagnosis of HIVAN or other HIV-related renal diseases. Groups progressing and not progressing to ESRD were compared using longitudinal analyses to assess the association between creatinine clearance and clinical and therapeutic factors. Results: The cohort consisted of 16 African-Americans, 2 Caucasians and 1 Native American. Their modes of HIV infection were intravenous drug use (7), a history of men having sex with men (3) and heterosexual behavior (5). Patients were followed for a median of 16.6 months. Seven patients reached ESRD. Loss of creatinine clearance over time did not differ among genders, races, or patients with different modes of HIV infection. Longitudinal analyses demonstrated an association between protease inhibitors and prednisone and a slower decline in creatinine clearance in multivariable models (p = 0.04 and 0.003, respectively). Conclusions: The epidemiology and clinical course of HIV-related renal diseases is more heterogeneous than previously, described. This study suggests a benefit to the use of protease inhibitors and prednisone on the progression of these nephropathies.