Definitive reconstruction after excision of cutaneous and soft tissue malignancies is sometimes limited as a result of lack of native tissue coverage options, patient comorbidities, or pending permanent margin analysis. Acellular dermis (AlloDerm®) reconstruction offers an excellent coverage alternative in these situations. We describe our experience using AlloDerm for coverage of skin and soft tissue defects. An Institutional Review Board approved review of patients undergoing skin/soft tissue coverage with AlloDerm from 2006 to 2012 was performed. Clinicopathologic variables, early postoperative findings, and subjective final cosmetic outcome were analyzed. Sixty-seven patients underwent AlloDerm reconstruction. Melanoma (67%) was the most frequent diagnosis. The median defect size was 42 cm(2) (range, 2 to 340 cm(2)), involving predominantly the lower extremity (45%) or head and neck (32%). AlloDerm was intended for use as a temporary dressing in 64 per cent (43 of 67) and permanent coverage in 24 (36%). Ten patients required reexcision for positive margins. Twenty-five (37%) underwent split-thickness skin graft or flap coverage after AlloDerm placement. Radiation was administered to 16 patients (24%) after AlloDerm reconstruction within a median of 53 days after surgery (range, 18 to 118 days). At first postoperative examination (median, 11 days after surgery), 85 per cent had evidence of healthy AlloDerm incorporation. Cellulitis was the most frequent complication (13%), all resolving with oral antibiotics. AlloDerm reconstruction after skin and soft tissue resection offers a suitable coverage alternative and may serve as a bridge to permanent reconstruction or as a permanent biologic dressing of complex surgical defects. In situations in which adjuvant radiation is needed, AlloDerm can be used without major complications.