Background <p>Empyema thoracis is a debilitating illness observed in all age groups. Recent data indicate increasing incidence rates and worsening outcomes. However, published data on the outcomes of empyema thoracis cases in our setting are scarce.</p> Objective <p>This study evaluated outcomes and associated factors for adult empyema thoracis patients managed at a single tertiary center in Uganda.</p> Methods <p>We reviewed the file records of patients 18 years or older who were managed for empyema thoracis at Mulago National Referral Hospital from January 2017 to December 2021. Sociodemographic data, comorbidities, clinical parameters at admission, and management strategies were reviewed. The outcomes of interest were in-hospital mortality and the need for re-intervention. A multivariate logistic regression model was used to identify independent factors associated with the need for re-intervention and in-hospital mortality.</p> Results <p>A total of 200 case files were analyzed, and 123 (61.5%) of the cases were males. The median age of the cohort was 33 years (IQR = 21). The in-hospital mortality rate was 10.5% (21 patients), and 23.5% (47 patients) required one or more re-interventions. Advancing age (adjusted OR = 1.04 (1.01–1.08)) and non para-pneumonic underlying etiology (adjusted OR = 11.45 (2.74–47.89)) were independently associated with increased in-hospital mortality, whereas delayed empyema drainage (adjusted OR = 2.97 (1.33–6.67)) and underlying non para-pneumonic etiology (adjusted OR = 3.83 (1.45–10.10.10)) significantly increased the odds of the need for re-intervention in management.</p> Conclusion <p>The in-hospital mortality and re-intervention rates for empyema thoracis were high in our study. Particularly at-risk groups for these poor outcomes are those with advanced age, non para-pneumonic empyema thoraces, and delayed initial intervention.</p>