A total of 115 Mycobacterium tuberculosis isolates from 80 patients were typed using IS6110-DNA fingerprinting and DR-based spoligotyping to describe the active transmission of tuberculosis in a Caribbean setting over a 2-year period. A total of 61 different pattern types were observed by IS6110-RFLP and 10 clusters containing between two and 15 patients could be defined. By spoligotyping, 45 different pattern types were observed with 12 clusters containing two to 11 patients. Thirty-two patients could be included in eight spoligotype-defined clusters and in nine RFLP-defined clusters when strictly concordant matching results were put together. In conclusion, about 40% of the patient isolates were clustered by DNA fingerprinting suggesting recent transmission of tuberculosis in our region. This study confirmed the increased accuracy and discriminatory power of the association of IS6110-RFLP and spoligotyping for studies on the molecular epidemiology of M. tuberculosis, and suggests that despite good implementation of tuberculosis control programs in Guadeloupe, active transmission of tuberculosis may be far more important than suspected.