Background <p>Mycobacterial pulmonary diseases remain a significant global health concern. This study investigates the interaction effects of relative humidity (RH), temperature, and fine particular matter (PM_2.5) with immune profiles, reflected by white blood cell (WBC) counts, on pulmonary drug-susceptible tuberculosis (DS-TB), multidrug-resistant TB (MDR-TB), and non-tuberculous mycobacteria (NTM) disease.</p> Methods <p>This case-control study of 1,398 participants, including 409 cases (203 DS-TB, 151 MDR-TB, and 55 NTM) and 989 controls, assessed individual exposure to RH, temperature, and PM_2.5, in mean and difference over 1-month interval, using radial basis function interpolation. Logistic regression models evaluated the associations between environmental exposures and these mycobacterial diseases while also analyzing their interaction effects with WBCs. Generalized additive models with penalized splines were used to explore potential non-linear associations.</p> Results <p>Higher mean RH was associated with a 0.92-fold decreased OR for DS-TB (95% CI: 0.88, 0.96), while higher temperature daily difference and PM_2.5 were associated with higher ORs across all mycobacterial disease groups. Non-linear models illustrated U-shape associations for those environmental factors. Additionally, elevated neutrophil levels attenuated the impact of temperature daily difference on NTM disease, while higher lymphocyte levels amplified temperature daily difference-related effects for DS-TB and MDR-TB.</p> Conclusion <p>This study highlights the role of WBC profiles in modifying the relationship between short-term temperature exposure and mycobacterial pulmonary disease, underscoring the interplay between environmental triggers and immune profiles in disease pathogenesis. Understanding these associations may enhance strategies for TB prevention and early detection.</p> Clinical trial number <p>Not applicable.</p>