Tuberculosis (TB) remains a significant global health challenge, with the World Health Organization (WHO) aiming for a 95% reduction in TB deaths by 2030. Disparities in TB detection persist, particularly regarding gender, immigration status, and resistance patterns. In Calabria, Italy-a key entry point for migrants from high-TB-incidence regions-TB poses a notable public health risk. This multicenter, retrospective study examines newly diagnosed TB cases in Calabria from 2012 to 2023, focusing on rifampicin-resistant TB (RR-TB). During this period, 800 TB cases were diagnosed, with 270 (33.7 %) in native-born Italians and 530 (66.2 %) in foreign-born individuals, showing significant differences in age (p <
0.001) and gender (p = 0.013). Among 685 patients of this cohort with available HIV status, 24 (3.5 %) were people living with HIV (PLWH), primarily from Africa, and diagnosed at higher rates of RR-TB (p <
0.001). TB cases varied by province, correlating with specific birthplaces. A total of 27 (3.4 %) RR-TB cases were identified, with heightened resistance to multiple drugs. Among these strains, 20 (74.1 %) were isoniazid-resistant (MDR-TB). This study underscores the need for comprehensive TB control strategies, especially regarding co-infection with HIV and the emergence of drug-resistant strains, emphasizing the importance of early detection and tailored management in Southern Italy.