Children contribute a substantial proportion of the global tuberculosis (TB) caseload, particularly in endemic areas, where little is known about their spectrum of disease. To document the complete disease spectrum, with relevant age- and HIV-related differences, in children treated for TB in a highly endemic community. A prospective descriptive study was conducted from February 2003 to October 2004 at five primary health care clinics in Cape Town, South Africa, including all children (< 13 years of age) treated for TB. In total, 439 children received anti-tuberculosis treatment. The spectrum of disease included 85 (19.4%) 'not TB', 307 (86.7%) intra-thoracic TB and 72 (20.3%) extra-thoracic TB (25 [5.7%] with co-existing intra- and extra-thoracic disease were included in both groups). In non-HIV-infected children, disseminated (miliary) disease (9/11, 81.8%) and tuberculous meningitis (TBM) (10/13, 76.9%) were predominantly documented in children < 3 years of age. In HIV-infected children, complicated Ghon focus and disseminated (miliary) disease were significantly more common (6/25, 24.0%) than in non-HIV-infected children (12/414, 2.9%) (OR 10.9, 95% CI 3.2-35.9). This study describes the complete disease spectrum observed in children treated for TB in a highly endemic area. Children suffered significant morbidity, with most severe disease recorded in very young and/or HIV-infected children.