Investigators hypothesize that high-dose n-3 polyunsaturated fatty acids (PUFA) oral supplementation will improve systemic inflammation, vascular function, and symptomatic status of patients with PAD. Investigators will explore novel mechanistic pathways by which n-3 PUFA affect PAD, evaluating the role of specialized lipid mediators involved in the resolution of inflammation.

The OMEGA-PAD II trial will be a 1:1 randomized, double-blinded trial comparing oral supplementation of n-3 PUFA (4.4g/day) to placebo in claudicants (Rutherford stage 1-3) for 3 months. Eligible patients will be screened according to specified inclusion and exclusion criteria. All patients will be treated per our current practice as reflected in the American Heart Association Practice guidelines on PAD. Blood draws, vascular function testing and 6-minute walking tests will be performed at baseline and after 3 months. n-3 PUFA supplementation will be achieved with 4 capsules of Pro-Omega twice daily (Nordic Naturals, Watsonville, California, USA), corresponding to a total of 4.4g/day. Each ProOmega capsule contains 325mg of EPA and 225mg of DHA. The placebo group will take the same number of capsules containing inactive substance (soybean; Nordic Naturals), designed to be the same color and shape as the treatment capsules.

Inclusion Criteria:

1. Intermittent claudication (Rutherford 1-3)

2. One of the following:

   1. Resting or exercise ankle-brachial index (ABI) <0.9
   2. toe pressure < 70 mm Hg
   3. documentation on imaging of greater than or equal to 50% stenosis in segments of aortoiliac arteries, femoral arteries, or tibial arteries

3. Age 50 and more

Exclusion Criteria:

1. Critical limb ischemia
2. Hypersensitivity/allergies to fish or seafood
3. Already on n-3 PUFA or equivalent
4. Significant renal, hepatic, and inflammatory disease
5. Concurrent severe infections
6. Acute illness (myocardial infarction, stroke, major surgery within 30 days)
7. Receiving immunosuppressive medications or steroids
8. Age < 50