Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m2, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II–IV, 6 months post transplant was 11% (95% CI, 4–32) and 39% (95% CI, 30–50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32–75) and 41% (95% CI, 33–52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4–33) and 18% (95% CI, 12–27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2–29) and 26% (95% CI, 18–36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66–96) and 56% (95% CI, 46–66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.