During last years, lung cancer treatment has rapidly changed thanks to novel drugs, such as immunotherapy and target therapy. Hence, an improvement of life expectancy, notwithstanding with a higher infectious risk. This is probably due to many factors, such as longer survival and immunosuppression; furthermore, novel drugs could increase infectious risk with different biologic mechanisms. However, correlation between infections and immunotherapy has not been completely clear, although lately has increasingly been described. Salmonella enterica spp is an intracellular facultative anaerobe gram-negative bacillus that can spread to different sites, such as lung and pleura; nevertheless, an association between lung cancer and pleural empyema due to salmonella infection is rarely highlighted in literature and its management is challenging. Hereby we outline the case of a 62-year-old woman affected by extended lung adenocarcinoma who developed salmonella-related pleural empyema during its active oncological treatment with chemo-immunotherapy by describing our multidisciplinary management model.