Background: Despite the scale-up of antiretroviral therapy (ART), active tuberculosis (TB) remains a major complication among people living with HIV (PLHIV). This study identified epidemiological risk factors for active TB among PLHIV receiving ART in Ibadan, Nigeria. Methods: A case–control study was conducted among 346 consenting PLHIV on ART (173 cases with active TB and 173 controls without TB) across selected hospitals in Ibadan, Nigeria. Data were collected using an interviewer-administered validated questionnaire and clinical records. Variables included socio-demographic, clinical, behavioral, psychosocial, and environmental factors. Data were analyzed using SPSS v.21 with level of significance at p ≤ 0.05. Results: Cases had significantly poorer clinical profiles than controls, with higher prevalence of unsuppressed viral load (69.4% vs. 32.4%, p<0.001) and CD4 count <200 cells/µL (89.6% vs. 75.7%, p=0.001). Mean ART adherence was lower among cases (11.76 ± 2.40) compared with controls (12.73 ± 1.86, p<0.001). Similarly, cases demonstrated less favorable attitudinal dispositions toward ART and TB treatment adherence than controls (17.02 ± 4.97 vs. 18.84 ± 3.66, p<0.001). In multivariate analysis, unsuppressed viral load (AOR=4.70; 95% CI: 2.80–7.87; p<0.05), CD4 count <200 cells/µL (AOR=2.60; 95% CI: 1.30–5.23; p<0.05), lower ART adherence (AOR=0.82; 95% CI: 0.71–0.94; p<0.05), and less favorable attitudinal dispositions toward treatment (AOR=0.87; 95% CI: 0.80–0.94;p<0.05) were independent predictors of HIV/TB co-infection with unsuppressed viral load being the most significant predictor (AOR=4.70; 95% CI: 2.80–7.87; p<0.05). Conclusion: Viral load, CD4 count, ART adherence, and attitudinal dispositions are significant predictors of HIV/TB co-infection, however, viral load appears to represent an important epidemiological goal of note in treatment outcomes. There is a need to strengthen integrated HIV/TB services with a focus on improving ART adherence and addressing attitudinal dispositions of the patients along with perceptions of expected outcomes and consequences through targeted counseling and support interventions. Clinical trial number: Not applicable