Persons living with HIV (PLWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART) risk suffering TDF-associated nephrotoxicity (TDFAN). TDFAN can result in short- and long-term morbidity, including permanent loss of kidney function, chronic kidney disease (CKD), and end-stage kidney disease (ESKD) requiring dialysis. Currently, there is no model to predict this risk or discern which patients to initiate TDF-based therapy. Consequently, some patients suffer TDFAN within the first few months of initiating therapy before switching to another suitable antiretroviral or a lower dose of TDF. In a prospective observational cohort study of adult Zambian PLWH, we modelled the risk for TDFAN before initiating therapy to identify individuals at high risk for experiencing AKI after initiating TDF-based therapy. We enrolled 205 HIV-positive, ART-naïve adults initiating TDF-based therapy followed for a median of 3.4 months for TDFAN at the Adult Infectious Disease Research Centre (AIDC) in Lusaka, Zambia. We defined TDFAN as meeting any of these acute kidney disease (AKD) criteria: 1) An episode of estimated glomerular filtration rate (eGFR)< 60ml/ min/1.73m2 within 3 months, 2) reduced eGFR by> 35% within 3 months or 3) increased serum creatinine by> 50% within 3 months. A total of 45 participants (22%) developed acute kidney disease (AKD) after TDF-based therapy. The development of AKD within the first 3 months of commencing TDF-based therapy was associated with an increase in baseline serum creatinine, age, baseline eGFR and female sex. We concluded that baseline characteristics and baseline renal function biomarkers predicted the risk for AKD within the first 3-months of TDF-based therapy.