Currently, COVID-19 and tuberculosis (TB) are the deadliest infectious diseases worldwide. Their synergy, form of presentation, morbidity, and mortality are data that have been scarcely explored. Thus, this study aimed to characterize the clinical, epidemiological, and laboratory factors of this co-infection and to analyze the factors associated with the active TB among COVID-19 cases. A case-control study was conducted with a retrospective survey of 21 laboratory-confirmed COVID-19/TB co-infected patients (case group) and 21 COVID-19 patients (control group). The study included participants from eight hospitals in Campo Grande city, capital of Mato Grosso do Sul State, Brazil, from March 2020 to March 2022. Association analysis and binomial logistic regression were employed with statistical significance set at p≤0.05. From the 21 identified cases of COVID-19/TB co-infection, we found a more frequent association with HIV infection than the control-group, without worsening the outcome. COVID-19/TB patients had less dyspnea and less need for mechanical ventilation compared to the cases with COVID-19 only. On the other hand, COVID-19/TB patients had higher levels of C-reactive protein and lower hemoglobin levels, the latter variable was independently associated with COVID-19/TB. Among the clinical differences presented among COVID-19/TB co-infected patients, despite the association with HIV and lower clinical repercussions, only lower hemoglobin levels were associated with COVID-19/TB.