BACKGROUND Historically, depressed skull fractures that warranted surgery were treated in 2 stages: the first stage involved debridement and craniectomy, followed by the second stage of delayed cranioplasty. More recently, single-stage autologous cranioplasty has been proven to be safe. However, there is a paucity of literature regarding single-stage titanium mesh cranioplasty when autologous repair is not possible. METHODS A retrospective review identified 22 patients who underwent single-stage titanium mesh cranioplasty for the acute treatment of comminuted depressed skull fractures. Fracture location, fracture etiology, timing of surgery, neurologic complications, infection, and cosmetic deformity were recorded. Average follow-up was 9 months. RESULTS The mean age of the patients was 34 years (range: 3-77); 83% were male. Seventeen (77%) involved the frontal bone, with 7 (32%) involving the frontal sinus. Eighteen (82%) had open defects at presentation. Sixteen (73%) were neurologically normal. Average time from presentation to repair was 11 hours (range: 1-28 hours). There were no neurologic worsening, seizures, or infections postoperatively. Antibiotic prophylaxis was prescribed in 13 cases (57%). One patient required revision surgery for persistent cosmetic deformity. CONCLUSIONS Autologous cranioplasty for depressed skull fractures is not always possible especially in cases of significant comminution. From our case series, single-stage titanium mesh cranioplasty appears to be a safe option.