Objectives: To describe cardiovascular disease (CVD) risk factors in adolescents and young adults with myelomeningocele (MMC) and to explore relationships with physical activity, aerobic fitness, and body fat. Design: Cross-sectional study. Setting: Outpatient clinic. Participants: Adolescents and young adults (N=31) with MMC (58% men) age 16 through 30 years; 13 were ambulatory and 18 were nonambulatory. Interventions: Not applicable. Main Outcome Measures: We studied biologic and lifestyle-related CVD risk factors, including lipid and lipoprotein profiles, blood pressure, aerobic fitness (Vo(2)peak), body fat, daily physical activity, and smoking behavior. We considered subjects at increased CVD risk when 2 or more of the following risk factors clustered: systolic blood pressure, total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and cigarette smoking. Relationships were studied using regression analyses. Results: Levels of TC, low-density lipoprotein cholesterol, and triglycerides were elevated in 29%, 38%, and 3% of the participants, respectively. HDL-C was reduced in 19%. Hypertension was found in 20%, and 19% were current cigarette smokers. Based on the clustering of risk factors, 42% of the participants were at increased CVD risk: 15% of ambulatory participants and 61% of nonambulatory participants (P=.03). Adjusted for sex and ambulatory status, participants with higher aerobic fitness tended to be more likely to have no CVD risk (odds ratio=13.0; P=.07). CVD risk was not associated to physical activity and body fat. Conclusions: A large proportion of the study sample was at CVD risk, indicated by clustering of risk factors. Improving aerobic fitness in young adults with MMC may contribute in reducing CVD risk; this needs to be confirmed in future studies.