BACKGROUND: Dengue hemorrhagic fever (DHF) is a severe form of dengue, characterized by bleeding and plasma leakage. A number of DHF risk factors had been suggested. However, these risk factors may not be generalized to all populations and epidemics for screening and clinical management of patients at risk of developing DHF. This study explored demographic and comorbidity risk factors for DHF in adult dengue epidemics in Singapore in year 2006 (predominantly serotype 1) and in year 2007-2008 (predominantly serotype 2). METHODS: A retrospective case-control study was conducted with 149 DHF and 326 dengue fever (DF) patients from year 2006, and 669 DHF and 1,141 DF patients from year 2007-2008. Demographic and reported comorbidity data were collected from patients previously. We performed multivariate logistic regression to assess the association between DHF and demographic and co-morbidities for year 2006 and year 2007-2008, respectively. RESULTS: Only Chinese (adjusted odds ratio [AOR] = 1.90; 95% confidence interval [CI]: 1.01-3.56) was independently associated with DHF in year 2006. In contrast, age groups of 30-39 years (AOR = 1.41; 95% CI:1.09-1.81), 40-49 years (AOR = 1.34; 95% CI:1.09-1.81), female (AOR = 1.57; 95% CI:1.28-1.94), Chinese (AOR = 1.67; 95% CI:1.24-2.24), diabetes (AOR = 1.78; 95% CI:1.06-2.97), and diabetes with hypertension (AOR = 2.16; 95%CI:1.18-3.96) were independently associated with DHF in year 2007-2008. Hypertension was proposed to have effect modification on the risk of DHF outcome in dengue patients with diabetes. Chinese who had diabetes with hypertension had 2.1 (95% CI:1.07-4.12) times higher risk of DHF compared with Chinese who had no diabetes and no hypertension. CONCLUSIONS: Adult dengue patients in Singapore who were 30-49 years, Chinese, female, had diabetes or diabetes with hypertension were at greater risk of developing DHF during epidemic of predominantly serotype 2. These risk factors can be used to guide triaging of patients who require closer clinical monitoring and early hospitalization in Singapore, when confirmed in more studies.