Objectives: To investigate if urban Africans displayed lower levels of atheroprotective high-density lipoprotein cholesterol (HDLC) when presenting with communicable versus non-communicable forms of heart disease (HD) as both acute infection and chronic inflammation reduce HDLC levels. Design: Hospital registry of 5328 de novo cases of HD over a 3-year period. Setting: Cardiology Unit, Baragwanath Hospital in Soweto, South Africa. Participants: A total of 1199 patients of African descent (59% women; 57.0±13.4 years) had fasting blood lipid levels (total cholesterol (TC), triglyceride, HDLC and low-density lipoprotein cholesterol (LDLC)) documented on admission. Serum inflammatory marker C reactive protein (CRP) was measured in a subset of 367 patients (31% of cases). Main outcome measures: Lipid profiles were compared according to prespecified classification of non-communicable (eg, hypertensive HD) versus communicable (eg, rheumatic HD) HD. Low HDLC was defined as <1.0 mmol/L for men and <1.2 mmol/L for women, according to applicable South African Clinical Guidelines. Results: Overall 694 (58%) of those presenting with HD had low HDLC levels; 344 of 678 (51%) and 350 of 521 (67%) for non-communicable and communicable, respectively (p<0.001). Comparatively, overall prevalence of high TC was 32% and high LDLC was 37%. On an adjusted basis, those with noncommunicable HD were more likely to record a low HDLC relative to non-communicable presentations (odds ratio (OR) 1.91, 95% CI 1.42 to 2.57; p<0.001). There was a strong relationship between low HDLC and higher levels of CRP, but only in women. Conclusions: Despite largely favourable lipid profiles, there are clear differences according to aetiology of underlying HD in urban Africans, with younger patients with communicable HD having particularly low levels of HDLC. Appropriate prospective evidence is needed to determine if persistent low levels of HDLC expose patients to increased, long-term risk of atherosclerotic forms of HD. The women-only inverse association between HDLC and CRP warrants further investigation.