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Important epidemiological changes and improvement of new diagnostic approaches, mainly molecular tools, might have impacted the management and outcome of tuberculosis (TB) in the last years in industrialized countries. In order to describe the epidemiological trends, and changes in clinical, diagnostic, and therapeutic aspects in patients with TB, an observational study was performed in a tertiary hospital in Western Europe (Madrid, Spain).All adult patients (>16 years) with a diagnosis of TB in the period 1995 to 2013 were included in the study.TB was diagnosed in 1284 patients, including 304 (24%) foreign-born and 298 (23.2%) human immunodeficiency virus (HIV)-infected patients. The proportion of foreign-born patients increased significantly, from 7.4% (1995) to 40.3% (2013), P < .001, while the proportion of patients with HIV infection decreased (from 41% to 15%, P < .001). Extrapulmonary locations of TB increased (from 23.9% to 37.1%, P < .001), although the miliary forms were less frequent (from 16% to 5.6%, P < .001). Pulmonary involvement remained constant during the period of study (from 50% to 46%, P = .18). The yield of microbiological diagnostic methods in different clinical specimens has remained very similar. Only molecular techniques have improved the diagnosis in respiratory, urinary, and peritoneal samples. The global cure rate was 64.8% and mortality rate was 9.1% (6.5% directly attributable to TB). Mortality has decreased significantly during the years of study (from 11% to 2%, P < .001).There has been a significant decline in the number of patients with TB. Changes in HIV coinfection and immigration have conditioned other epidemiological and clinical aspects of the disease, including the clinical presentation, treatment response, and mortality. Only the use of molecular tests has provided an improvement in the diagnosis of pulmonary and extrapulmonary TB.