Objective: In April 2010 the South African government added Tenofovir disoproxil fumarate to its first-line antiretroviral therapy (ART) for HIV patients. We analyzed the relationship between renal dysfunction at tenofovir initiation, nephrotoxicity and mortality. Design: Retrospective cohort analysis of HIV-infected adults who received tenofovir and had a creatinine clearance done at initiation at the Themba Lethu Clinic, Johannesburg, South Africa between April 2004-September 2009. Methods: We estimated the relationship between renal dysfunction, nephrotoxicity [any decline in kidney function from baseline (acute or chronic) that is secondary to a toxin (including drugs)] and mortality for patients initiated on tenofovir-containing regimens using marginal structural models and inverse probability of treatment weights to correct estimates for lost to follow-up and confounding. Results: Of 890 patients initiated on tenofovir, 573 (64.4%) had normal renal function (>90ml/min), 271 (30.4%) had mild renal dysfunction (60-89ml/min) and 46 (5.2%) had moderate renal dysfunction (30-59ml/min). 2.4% experienced nephrotoxicity, 7.8% died and 9.7% were lost during 48-months of follow-up. Patients with mild (HR 4.8; 95%CI: 1.5-15.2) or moderate (HR 15.0; 95%CI: 3.4-66.5) renal dysfunction were at greatest risk of nephrotoxicty, while those with mild (HR 1.2; 95%CI: 0.7-2.3) or moderate (HR 3.2; 95%CI: 1.3-7.8) renal dysfunction vs. normal renal function were at highest risk of death by 48-months. Conclusion; Much of the incident renal dysfunction in tenofovir patients is likely related to pre-existing renal pathology, which may be exacerbated by tenofovir. With expanded use of tenofovir, screening for renal dysfunction prior to initiation and dose adjustment is necessary to help improve ART outcomes.