Lesotho introduced tenofovir disoproxil fumarate (TDF) for first-line antiretroviral treatment (ART) in 2008. The use of TDF has been associated with renal toxicity. The study utilised an analytical design to compare retrospective creatinine clearance (CrCl) data of 312 antiretroviral treatment naïve adults exposed to TDF and 173 unexposed patients. Impaired renal function was defined as CrCl<50 ml/min calculated using the Cockcroft-Gault equation. In fifty-six patients (17.9%) TDF was found to be contraindicated. The use of TDF was marginally significant factor for renal toxicity (p=0.054) in univariate analysis, but was insignificant (p=0.122) in multivariate logistic analysis. Univariate (p<0.1) and multivariate logistic regression (p<0.05) were performed using STATA® 11. Female gender (p=0.016), hypertension (p=0.009), and age > 60 (p=0.004) were significantly associated with CrCl<50 ml/min outcome. TDF is a weak contributing factor to renal impairment. Routine baseline renal function screening should be adopted to prevent patients with impaired renal function receiving TDF.