Introduction Intermittent claudication is the leading symptom of peripheral artery disease (leg pain when walking). The present study investigates the extent to which walking impairment is associated with health-related quality of life, mental health and health risk behavior. Methods A theory-based, cross-sectional path model was empirically examined using pre-intervention baseline data from a multicenter, randomized-controlled trial of patients with intermittent claudication (PAD-TeGeCoach). Data were available from 1 696 patients who completed a battery of questionnaires between April 14, 2018 and March 12, 2019, including measures of walking impairment (Walking Impairment Questionnaire), health-related quality of life (SF-12), mental burden (GAD-7, PHQ-9), nicotine- and alcohol-related risk behavior (Fagerström-Test, AUDIT-C). Sociodemographic characteristics and comorbid conditions were included in the postulated model a priori to minimize confounding effects. Results Walking impairment was associated with an increase in depressive (β = -.36, p < .001) and anxiety symptoms (β = -.24, p < .001). The prevalence of depressive and anxiety symptoms was 48.3% and 35.5%, respectively, with female patients and those of younger age being at greater risk. Depressive symptoms were predictive of an increased tobacco use (β = .21; p < .001). Walking impairment had adverse effects on physical quality of life, both directly (β = .60, p < .001) and indirectly mediated through depressive symptoms (β = -.16, p < .001); and indirectly on mental quality of life mediated through depressive (β = -.43, p < .001) and anxiety symptoms (β = -.35, p < .001). Discussion The findings underscore the need for a comprehensive treatment strategy in patients with intermittent claudication. Measures to improve walking impairment (e.g. exercise training) are key to enhance quality of life and should be the primary treatment. As a key mediator of mental quality of life, depressive and anxiety symptoms should be addressed by rigorously including mental health treatment. Risky health behaviors should be approached by promoting behavior change (e.g. smoking cessation) as a secondary prevention of peripheral artery disease.