Household-based tuberculosis (TB) contact evaluation may be an efficient strategy to reach people who could benefit from oral pre-exposure prophylaxis (PrEP) because of the epidemiological links between HIV and TB. This study estimated the number of HIV serodifferent couples in TB-affected households and potential HIV acquisitions averted through their PrEP use in 4 TB-HIV high-burden countries. We conducted a model-based analysis set in Ethiopia, Kenya, South Africa, and Uganda using parameters from population-based household surveys, systematic literature review and meta-analyses, and estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. We parameterized the nonlinear relationship between the proportion of serodifferent couples among people living with HIV and population-level HIV prevalence using Markov chain Monte Carlo methods. We integrated all parameters in a mathematical model and propagated uncertainty using a Monte Carlo approach. We estimated the HIV prevalence among adults aged 15-49 living in TB-affected households to be higher than in the general population in all 4 countries. The proportion of serodifferent couples among all couples in TB-affected households was also higher than in the general population (South Africa: 20.7% vs. 15.7%, Kenya: 15.7% vs. 5.7%, Uganda: 14.5% vs. 6.0%, Ethiopia: 4.1% vs. 0.8%). We estimated that up to 1,799 (95% UI: 1,256-2,341) HIV acquisitions in South Africa could be prevented annually by PrEP use in serodifferent couples in TB-affected households, 918 (95% UI: 409-1,450) in Kenya, 686 (95% UI: 505-871) in Uganda, and 408 (95% UI: 298-522) in Ethiopia. As couples in TB-affected households are more likely to be serodifferent than couples in the general population, offering PrEP during household TB contact evaluation may prevent a substantial number of HIV acquisitions.