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Managing the simultaneous treatment of HIV/AIDS and tuberculosis (TB) increases the risk of adverse reactions, drug interactions, and challenges to treatment adherence. To address these complexities, a multidisciplinary approach is crucial for preventing, identifying, and resolving drug therapy problems (DTPs) in these patients. Therefore, this study aimed to assess the magnitude and associated factors of DTPs in hospitalized people with tuberculosis and those living with HIV/AIDs at two referral hospitals. We conducted a prospective observational study between January 2024 and May 2024 in the infectious diseases unit of the internal medicine department at the University Teaching Hospitals (UTHs) and Levy Mwanawasa University Teaching Hospital (LMUTH) . Cipolle’s and Strand’s DTP classification system was used to identify DTPs. Multiple logistic regression was used to evaluate the factors associated with drug-therapy problems. A total of 139 patients were evaluated, of whom 117 (84.2%) presented with at least one drug therapy problem, with indication and effectiveness-relate problems being the most frequent.. The most common DTP was sub-therapeutic dosing, accounting for 92 (35.7%) cases. Of these, 74 (80%) were due to Dolutegravir sub-therapeutic dose, while 18 (20%) involved anti-tuberculosis medications. Poor adherence was the second most common DTP, occurring in 51 (19.8%) cases . The physician’s acceptance rate of clinical pharmacists’ interventions was 137 (98.1%). According to the multivariable, having tertiary education (AOR = 0.084, 95% CI: 0.011–0.66, p = 0.019), being divorced/widowed (AOR = 0.21,95% CI:0.056–0.79, p = 0.021) living outside Lusaka( Capital city) (AOR = 0.23,95% CI:0.054–0.995, p = 0.049) and self-employed(AOR = 0.02,95% CI:0.006–0.65, p = 0.021) were significantly associated with lower likelihood of with DRPs while being married (IRR = 1.58,95% CI:1.17–2.14, p = 0.003) and unemployed (IRR = 1.34,95% CI:1.04–1.76, p = 0.04) were associated with a higher incidence rate of DTPs. Drug therapy problems were highly prevalent among co-infected patients with HIV/AIDS and tuberculosis, with sub-therapeutic dosing and poor adherence being the most common. The high physician acceptance rate of clinical pharmacists’ interventions underscores the value of clinical pharmacy services in optimizing patient care. These findings highlight the need to strengthen clinical pharmacy services, particularly by increasing clinical pharmacists' involvement in multidisciplinary ward rounds to reduce drug therapy problems and optimize patient care.