Mycobacterial infections are complex diseases and are even more in individuals suffering from immune-mediated inflammatory diseases (IMIDs). They can cause tuberculosis, nontuberculous mycobacteria (NTM) pulmonary infections, other localized NTM or disseminated infections, leprosy, and chronic ulcers (Buruli ulcer). IMID-afflicted patients are at increased risk, often have atypical clinical presentations and unusual or complicated clinical courses during therapy. Providers taking care of individuals with IMID must have some knowledge about mycobacterial infections to recognize and diagnose the disease. They should not treat those infections alone and should look for expert guidance. Treatment usually implies multiple drugs that can cause severe side effects. This hazard can be reduced with judicious selection of therapeutic agents and close monitoring. Prevention of disease acquisition, reactivation, and recurrence should also be sought.