Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is well-documented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TB-induced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.