OBJECTIVE: To determine the association between the physical activity vital sign (PAVS) and markers of cardiometabolic disease. DESIGN: Patients were assessed through the PAVS, a validated tool self-reporting the frequency and duration of physical activity. Patients were categorized into 3 groups: inactive (0 minutes per week), underactive (1-149 minutes per week), and active (>150 minutes per week). Associations were tested between the PAVS and the cardiometabolic disease biomarkers of body mass index, hemoglobin A1c (A1c), blood pressure, and low-density lipoprotein (LDL) using one-way analyses of variance. SETTING: High-risk family medicine residency clinic. PARTICIPANTS: Two thousand three hundred twenty-one adult patients (age ≥ 18 years). RESULTS: Participants reported a mean of 97.87 (SD = 149.35) minutes per week of exercise. Overall, 50.1% reported physical inactivity, 25.7% were underactive, and 24.3% were active. Younger individuals (P < 0.001) and men (P < 0.05) reported more physical activity than older individuals and women. Patients who reported being active were significantly less likely to be overweight (P < 0.05), obese (P < 0.05), or hypertensive (P < 0.05), but there was no association with A1c or LDL levels. CONCLUSIONS: This is the first investigation to examine the PAVS in a high-risk population. In these patients, reported levels of physical inactivity are 150% higher than other clinical settings, and the PAVS is only associated with improvements in 2 of 4 major cardiometabolic risk factors. For this group, self-reported levels of physical activity may need to be higher for cardiovascular benefits to be realized in all 4 cardiometabolic domains. The PAVS offers health professionals an opportunity to encourage lifestyle-based interventions to reduce cardiovascular risk, but refinements may be necessary to address this population.