The protective role of high high-density lipoprotein cholesterol (HDL-C) against cardiovascular risk has been questioned recently. Due to the increasing trend of cardiovascular diseases (CVD) in Tunisia, this study aimed to determine the prevalence of high HDL-C and its associated factors in Tunisian women of childbearing age. A cross-sectional survey was conducted among a subsample of 1689 women, aged 20 to 49 years, in the Great Tunis region. Data on socio-demographic and lifestyle factors were collected by a questionnaire. Overall adiposity was assessed by body mass index (BMI). All biological variables were assayed in blood samples coated with anticoagulant ethylene diamine tetra acetic acid (EDTA) by enzymatic methods. Stata software (2015) was used for data management and statistical analysis. High HDL-C values were recorded in 26.6% of selected women. After adjustment for all socio-demographic and lifestyle factors, age, hypertension, and smoking were negatively associated with high HDL-C levels, while family history of cancer was positively associated with high HDL-C in women. An additional investigation on the relationship between high HDL-C and cancer risk should be performed due to controversial results.