Infections caused by mycobacteria, including both the Mycobacterium tuberculosis complex and non-tuberculous mycobacteria, represent a significant cause of morbidity in immunocompromised patients. Deficient cellular immunity predisposes to atypical and diagnostically challenging presentations. This report highlights two such cases, emphasizing the need for careful clinical evaluation and a multidisciplinary approach.Case 1: A 28-year-old woman, self-employed, immunocompromised due to anti-TNF therapy for Crohn’s disease, presented to the Family Health Unit with a painful ulcerative vulvar lesion. She was referred to the emergency department, where a biopsy was performed, revealing epithelioid granulomas and confirming Mycobacterium tuberculosis infection. Case 2: A 27-year-old man, self-employed, on antiretroviral therapy for HIV infection and co-infected with HCV, under follow-up in the hospital’s Infectious Diseases department, presented to the Family Health Unit with four days of rectal bleeding and was initially treated for probable hemorrhoidal disease. One month later, he returned due to persistent post-defecation rectal bleeding, associated with diarrhea—approximately 10 loose stools per day—and intermittent low-grade fever. On physical examination, an elongated erythematous protrusion was observed on the anal mucosa. He was referred to the emergency department, where stool cultures for mycobacteria identified Mycobacterium intracellulare.These cases illustrate rare presentations of mycobacterial infections in immunocompromised patients. Case 1 involved a vulvar M. tuberculosis lesion in a woman on anti-TNF therapy, while case 2 featured gastrointestinal M. intracellulare in an HIV/HCV coinfected patient, initially mimicking hemorrhoidal disease. Although such infections are documented, their atypical manifestations highlight unique diagnostic challenges.These cases highlight the need for high clinical suspicion of opportunistic infections in immunocompromised patients, even when symptoms appear common. Early diagnosis requires thorough evaluation and targeted laboratory testing. Future practice should emphasize routine screening in high-risk populations and multidisciplinary collaboration to minimize diagnostic delays.These cases highlight the challenges of diagnosing opportunistic infections in immunocompromised patients. Accurate diagnosis requires careful consideration beyond common clinical assumptions and relies on combining clinical evaluation with laboratory and histopathological findings.These cases emphasize the value of updated protocols, multidisciplinary care, and professional training to enable early detection, optimize patient outcomes, and support public health planning.