Background: The objective of this study was to examine the relation of high-density lipoprotein cholesterol (HDL-C) to coronary heart disease in Japanese men whose serum total cholesterol is low by Western standards. Methods and Results: A prospective, observational study based on 7.7 years of follow-up for incidence of coronary heart disease and stroke was conducted. The subjects were 6408 middle-aged male workers aged 40 to 59 years at baseline in urban companies in Osaka, Japan, whose mean serum total cholesterol was 5.10 mmol/L. Mean HDL-C adjusted for age, total cholesterol, systolic blood pressure, alcohol intake, cigarette smoking, and body mass index was 1.27 to 1.28 mmol/L for men who developed coronary heart disease (n = 46) or definite myocardial infarction (n = 21) compared with 1.46 mmol/L for those free of cardiovascular disease (n = 6256; difference, P<.01). There was no significant difference in mean HDL-C between stroke cases (n = 33) and those free of cardiovascular disease. The incidence rates of coronary heart disease and definite myocardial infarction, adjusted for the other risk factors, were three to four times higher in the lowest HDL-C quartile (<1.24 mmol/L) than the highest quartile (≥1.66 mmol/L), and there was a significant dose response for definite myocardial infarction. Serum total cholesterol was positively and significantly associated with coronary heart disease incidence. Furthermore, the inverse association for HDL-C was apparent among men with total cholesterol <5.69 mmol/L (mean total cholesterol, 4.76 mmol/L) and men with total cholesterol ≥5.69 mmol/L (mean total cholesterol, 6.26 mmol/L). Conclusions: Coronary heart disease incidence in inversely related to HDL-C in urban Japanese middle-aged men, whose mean total cholesterol (5.10 mmol/L) is relatively low.