PURPOSE: Tuberculosis (TB) remains a leading cause of morbidity and mortality, with 1.3 million deaths in 2022. Extrapulmonary tuberculosis (EPTB) accounts for approximately 20% of all TB cases. We assessed the clinical presentation and challenges during the course of treatment in EPTB patients in a low-incidence setting. METHODS: We conducted a prospective cohort study involving 44 EPTB patients at the University Hospital of Cologne, Germany. Clinical data were collected before and during treatment. RESULTS: The cohort comprised 44 patients originating from 21 countries. Two or more invasive procedures were required for microbiological confirmation in 59% (26/44) of the cases. Sputum culture was positive in 18% (8/44) of patients, with 63% (5/8) showing no radiological signs of pulmonary involvement. The median therapy duration was ten months and increased with disease severity. Paradoxical reactions (PR) occurred in 31% (13/42) of the patients. A previously published clinical scoring system assessing EPTB treatment responses showed a favorable treatment outcome in only 68% (21/31) of the patients in this cohort. CONCLUSION: EPTB exhibits highly variable disease severity and organ involvement. Treatment initiation is often delayed due to diagnostic challenges. Management is complicated by the frequent occurrence of PR, which can lead to treatment durations exceeding standard recommendations. Clinical scores for treatment response assessment may not be reliably applicable, highlighting the need for alternative biomarkers.