Demineralized bone matrix (DBM) has been shown to have positive effects on union rates in many orthopedic subspecialties; however, minimal evidence exists about bone graft substitutes in foot and ankle surgery. The purpose of this study is to compare nonunion rates in arthroscopic ankle arthrodesis in patients receiving DBM with those without. We hypothesized DBM to be associated with a decreased risk of nonunion. This retrospective review includes 516 consecutive ankle arthrodesis cases from March 2002 to May 2016. Of these, 58 ankles (56 patients) that underwent primary arthroscopic ankle arthrodesis met the inclusion criteria, and 31 of these ankles received DBM, while 27 did not. Nonunion was assessed by clinical examination and routine postoperative radiographs. If nonunion was suspected, a computed tomography (CT) scan was performed. The primary outcome measure was nonunion rate. Secondary outcome measures included wound complications, return to operating room (OR), and rate of postoperative deep vein thrombosis (DVT) or pulmonary embolism (PE). From the study cases, 58 were available for final follow-up. The average age was 55.9 years (±17.4), and mean follow-up was 43.0 months (range 6.3–119.4). There was no difference in nonunion rate in patients who received DBM (4/31, 12.9%) versus those who did not (4/27, 14.8%) (p = 0.83). Similarly, when comparing the two groups, there were no statistically significant differences in superficial wound complications (6.5% vs. 3.7%, p = 1.0) or rate of return to OR (29% or 0.037/person-years vs. 37% or 0.099/person-years; p = 0.20). No major complications including deep wound infections, DVTs, or PEs occurred. This is the largest study to directly compare nonunion rates and complications for patients receiving DBM versus those who did not in primary arthroscopic ankle arthrodesis. No significant association was found between DBM usage and risk of nonunion, wound complications, return to OR, or postoperative DVT or PE development.