The objective of this study was to determine whether lower extremity peripheral arterial disease (PAD) is associated with depressive symptoms and whether PAD-related disability mediates the association between PAD and depressive symptoms. The study used a cross-sectional design set in an academic medical center. A cohort of men and women aged 55 years and older with (n = 93) or without (n = 74) PAD was recruited. PAD subjects were identified from a blood flow laboratory and a general medicine practice. Non-PAD subjects were identified from the same general medicine practice. PAD was diagnosed and quantified using the ankle-brachial index (ABI). Depressive symptoms were assessed by the 15-item short version of the Geriatric Depression Scale (GDS-S; score range 0-15, 0 = no depressive symptoms). The six-minute walk test and the Walking Impairment Questionnaire (WIQ) distance score (score range 0-100, 100 = better walking ability) were measures of walking impairment. PAD subjects had depressive mood (DM) (defined by GDS-S score >5) twice as often as controls (24% vs 12%, p = 0.06). After adjustment for age, education, and number of comorbidities, the prevalence of depressive mood among PAD subjects was increased, but this association was not significant (OR = 1.8, 95% CI 0.7-4.4). The WIQ distance score weakened the association between PAD and DM, and higher distance scores were associated with a lower likelihood of DM (OR = 0.98 per one unit of the WIQ, 95% CI 0.96-0.99). Among PAD subjects, severe PAD (ABI <0.5) was not significantly associated with DM (OR = 1.4, 95% CI 0.5-4.1), but a greater 6-min walk distance was associated with a lower likelihood of DM (OR = 0.8 per 100 feet, 95% CI 0.70-0.97). Substituting the WIQ scores for six-min walk distance in the model showed that higher WIQ scores were associated with lower likelihood of DM among PAD subjects (OR= 0.98 per one unit of the WIQ, 95% CI 0.95-1.0), though the association did not achieve statistical significance. In conclusion, these data suggest that PAD may be associated with an increased risk of DM and that this relationship may be related to PAD-associated disability. An evaluation for depression may be appropriate in men and women with PAD. Findings should be evaluated in a larger study cohort.