Background: The Heart of Soweto Study aims to increase our understanding of the characteristics and burden imposed by heart disease in an urban African community in probable epidemiological transition. We aimed to investigate the clinical range of disorders related to cardiovascular disease in patients presenting for the first time to a tertiary-care centre. Methods: From Jan 1 to Dec 31, 2006, we recorded data for 4162 patients with confirmed cases of cardiovascular disease (1593 newly diagnosed and 2569 previously diagnosed and under treatment) who attended the cardiology unit at the Chris Hani Baragwanath Hospital in Soweto, South Africa. We developed a prospectively designed registry and gathered detailed clinical data relating to the presentation, investigations, and treatment of all 1593 patients with newly diagnosed cardiovascular disease. Findings: Most patients were black Africans (n=1359 [85%]), and the study population contained more women (n=939 [59%]) than men. Women were slightly younger than were men (mean 53 [SD 16] years vs 55  years; p=0·031), with 399 (25%) patients younger than 40 years. Heart failure was the most common primary diagnosis (704 cases, 44% of total). Moderate to severe systolic dysfunction was evident in 415 (53%) of 844 identified cases of heart failure, 577 (68%) of which were attributable to dilated cardiomyopathy or hypertensive heart disease, or both. Black Africans were more likely to be diagnosed with heart failure than were the rest of the cohort (739 [54%] vs 105 [45%]; odds ratio [OR] 1·46, 95% CI 1·11-1·94; p=0·009) but were less likely to be diagnosed with coronary artery disease (77 [6%] vs 88 [38%]; OR 0·10, 0·07-0·14; p<0·0001). Prevalence of cardiovascular risk factors was very high, with 897 (56%) patients diagnosed with hypertension (190 [44%] of whom were also obese). Only 209 (13%) patients had no identifiable risk factors, whereas 933 (59%) had several risk factors. Interpretation: We noted many threats to the present and future cardiac health of Soweto, including a high prevalence of modifiable risk factors for atherosclerotic disease and a combination of infectious and non-communicable forms of heart disease, with late clinical presentations. Overall, our findings provide strong evidence that epidemiological transition in Soweto, South Africa has broadened the complexity and spectrum of heart disease in this community. This registry will enable continued monitoring of the range of heart disease.