Background: The coexistence of chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) complicates diagnosis and treatment, increasing disease burden and mortality. The correlation between serum inflammatory factors and disease severity and prognosis in COPD patients with TB remains unclear. Methods: This retrospective study included 200 participants treated at the Affiliated Hospital of Hebei University from December 2020 to December 2022: 80 patients with COPD and TB, 40 with COPD alone, 40 with TB alone, and 40 healthy controls. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), soluble IL-2 receptor (sIL-2R), and C-reactive protein (CRP) were compared across groups and correlated with disease severity and prognosis in COPD patients with TB. Results: Serum levels of TNF-alpha, IL-6, IFN-gamma, sIL-2R, and CRP were significantly higher in the COPD with TB group compared to all other groups (P<0.05). In this group, elevated levels of these markers were associated with increased disease severity and poorer prognosis (P<0.05). Correlation analysis showed positive associations between inflammatory cytokine levels and disease severity, and negative associations with prognosis (P<0.05). Conclusion: Serum inflammatory markers may help assess disease severity and prognosis in COPD patients with TB. However, due to the observational design, causality cannot be inferred. Further prospective, multi-center studies are required to validate these findings before clinical application.