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The optimal catheter-directed therapy for femoropopliteal in-stent restenosis (ISR) remains controversial with limited durability. The natural history of untreated ISR is not well characterized. We evaluated the midterm outcomes of patients with asymptomatic isolated femoropopliteal ISR who were observed under a surveillance program.Patients treated with isolated femoropopliteal stents from January 2009 to December 2013 were retrospectively investigated for the development of ISR. ISR was classified on the basis of duplex ultrasound criteria, with >50% defined as peak systolic velocity (PSV) twice that of the normal vessel and >75% as PSV >400 cm/s or four times the normal PSV. Asymptomatic patients with ISR of >50% were tracked for progression to high-grade (>75%) stenosis, occlusion, need for reintervention, and amputation.Asymptomatic ISR of >50% was identified in 62 (15.3%) of 402 patients with isolated femoropopliteal stents. The mean time for development of ISR was 22.1 (±20.1) months. The mean age was 72 (±9.7) years, and 34 (55.7%) patients were female. Thirty-one (50%) patients were diabetic, 18 (29.1%) were smokers, and 8 (12.9%) had chronic kidney disease. Indications for treatment were claudication in 49 (79.0%), tissue loss in 9 (14.5%), and rest pain in 4 (6.4%) patients. TransAtlantic Inter-Society Consensus (TASC) A lesions were treated in 13 (21%) patients, TASC B lesions in 24 (38.7%), and TASC C lesions in 25 (40.3%). Three-vessel runoff was identified in 25 (40.3%) patients, two-vessel runoff in 18 (29.0%), and one-vessel runoff in 19 (30.6%). Under surveillance, ISR of >50% progressed to >75% or occlusion in 20 (32.3%) patients. The mean time to progression was 17.4 months, and the mean overall follow-up was 33.1 months. Reintervention was required in 22 (35.0%) patients, with an average of 1.95 (range, 1-4) interventions per patient. Reintervention was undertaken in 19 (86%) patients for claudication and in 3 (18%) patients for critical limb ischemia. One patient required an amputation despite previous reintervention for progression. Progression to >75% stenosis was predictive of need for reintervention (P = .004).Under a surveillance program, asymptomatic patients with femoropopliteal ISR of >50% may be observed with a low risk of limb loss. Given the slow rate of progression and the poor durability of reintervention, surveillance with delayed intervention may be warranted.