Hemospray (Cook Medical, Winston-Salem, North Carolina, USA) is a hemostatic agent recently introduced for the management of upper gastrointestinal bleeding (GIB). To date, there is little experience with this fairly new hemostatic tool. The aim of this case series was to reflect the use and effectiveness of Hemospray as a treatment option in GIB in everyday clinical practice at two tertiary referral centers. Consecutive patients (n = 16) with active GIB of various origins were treated with Hemospray. The rate of successful initial hemostasis was 93.75 % (15 /16; salvage therapy 92.85 % [13/14]; monotherapy 100 % [2 /2]). The rebleeding rate within 7 days was 12.5 % (2/16). One patient, in whom interventional radiology also failed, had to undergo surgery as salvage therapy. The effectiveness of Hemospray in the management of GIB in various clinical situations is promising. Future multicenter randomized prospective trials for clearly defined bleeding situations are needed for greater generalizability of case series findings.