Introduction: Cardiovascular disease (CVD) is a leading cause of death and disability. Risk factors for CVD have been defined by the recent cholesterol guidelines panel as male gender, and increased age, blood pressure, and total cholesterol, as well as blood pressure treatment, current cigarette smoking, diabetes, and decreased high density lipoprotein (HDL) cholesterol. Our goal was to develop an improved model for predicting CVD risk over 10 years in middle aged male subjects in order to be able to identify high risk subjects. Methods: Using plasma or serum samples obtained from male subjects after an overnight fast who were participants in cycle 6 of the Framingham Offspring Study, we measured: C reactive protein (CRP), high density lipoprotein cholesterol (HDL-C), triglycerides, total cholesterol, direct low density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), lipoprotein(a), and apolipoprotein (apo) A-I content of HDL particles as separated by two dimensional gel electrophoresis. Blood pressure, body mass index, waist circumference, history of diabetes, and use of blood pressure, cholesterol, and glucose lowering medications was also assessed. Follow-up information including CVD status over a median of 12.3 years was available for 1,083 men, mean age 59 years and without CVD at onset, of whom 207 (19.1%) developed CVD. A model was developed to predict new onset CVD using only those variables that provided significant information in a stepwise logistic regression analysis to calculate the area under the curve (AROC) and C statistic. Results: The following variables entered the model and provided an overall C statistic of 0.73: 1. age, 2. blood pressure treatment, 3. Lp(a), 4. sdLDL-C, 5. ApoA-I in large α-1 HDL, 6. smoking, and 7. diabetes. This model was significantly superior to a model using the standard risk factors or one also using CRP (C statistic 0.68). Conclusions: Our data indicates that the measurement of LDL and HDL subfraction and Lp(a) provides significant additional information about CVD risk as compared to standard risk assessment which assesses only total cholesterol and HDL-C.