Blood pressure and cholesterol reduction have proven effective to reduce cardiovascular disease (CVD) risk, yet adherence to medical therapy is suboptimal and contributing factors to non-adherence are not well-established. The purpose of this study was to determine the prevalence and predictors of non-adherence to blood pressure and cholesterol-lowering medications in individuals who participated in an NHLBI-sponsored evaluation of a hospital-based screening and outreach program for high-risk employees and the community. This was a cross-sectional study of 371 adults (mean age 60 years, 57% female, 60% non-white) who were eligible to participate if they were men >40 years, women >50 years, or had established CVD or CVD-risk equivalent. Each participant received a comprehensive standardized CVD screening evaluation; medication non-adherence was defined as missing any pills for high blood pressure or abnormal cholesterol in the past week. Associations between participant demographics, lifestyle and psychosocial risk factors, and non-adherence were assessed using logistic regression to adjust for confounders. The prevalence of taking medication for high blood pressure or abnormal cholesterol in the study population was 48% and 38%, respectively. Among those participants, 14% reported missing high blood pressure pills and 23% reported missing cholesterol pills in the past week. Significant (p<0.05) univariate predictors of non-adherence to blood pressure medication were smoking, depression, feeling sad or blue for 2 weeks or more, and eating fast food ≥2 times per week. In a multivariable regression model adjusted for confounders, participants who reported missing any blood pressure pills in the past week were 6.6 times more likely to have uncontrolled hypertension (≥140/90 mmHg) compared to those who were adherent (95% CI = 2.1-20.2). Age <65 years and eating outside the home ≥2 times per week were significantly associated with non-adherence to cholesterol medication even after adjusting for measured confounders. Non-adherence to preventive medications was associated with poor blood pressure control and several lifestyle and psychosocial risk factors for CVD. This information may be clinically useful to help identify individuals who may be non-adherent to medical therapy and at increased CVD risk.