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Tuberculosis (TB) is a major global health concern and is responsible for significant morbidity and mortality, especially among people living with HIV (PLHIV). TB preventative therapy using isoniazid (IPT) for latent TB in PLHIV is a commonly recommended, although often underutilized, treatment to decrease progression to active disease, as well as reduce the possibility of onward disease transmission. This study investigates factors associated with IPT course completion in a large cohort of PLHIV in Botswana, focusing on the antiretroviral (ARV) therapy a patient is receiving. 57,359 PLHIV were evaluated for IPT, 40,379 (70.4%) patients initiated IPT, and 38,293 (94.8%) of these completed the course of therapy. Logistic regression modeling was used to evaluate the association between ARV regimen, as well as other independent variables of age, gender, pregnancy status, and daily pill burden, with the dependent outcomes of IPT completion, IPT initiation, side effects, and death. We found that certain ARV regimens were associated with the likelihood of IPT completion; when compared to the reference ARV of TDF/FTC/EFV, TDF/3TC/DTG was found to be associated with an increased likelihood of treatment completion (OR = 1.24; 95% CI = 1.08, 1.43), while AZT/3TC_EFV (OR = 0.75, 95% CI = 0.62, 0.90), AZT/3TC_NVP (OR = 0.82, 95% CI = 0.68, 1.00), and TDF/FTC_LPV/R (OR = 0.70, 95% CI = 0.51, 0.98) were found to be associated with a decreased likelihood of treatment completion. Part of this relationship is possibly secondary to the daily pill burden of those ARV regimens, as well as side effects that may occur with concomitant IPT. Additionally, ARV regimen, age, and gender, were found to be associated with initiation of IPT, suggesting that targeted educational interventions may be needed in specific groups to increase participation in IPT programs. These findings should be taken into consideration by clinicians and managers intending to increase the operational effectiveness of IPT programs.