Cangrelor is approved for use during percutaneous coronary intervention (PCI) and is administered with different parenteral anticoagulants. We examined the efficacy and safety of cangrelor in the subgroup of patients who received unfractionated heparin (UFH) during PCI in the modified intention-to-treat population of the randomized CHAMPION PHOENIX trial (cangrelor vs clopidogrel; n = 10,939). The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) at 48 hours. The key secondary efficacy end point was ST. UFH was used in 69.2% (7,569/10,939) of patients. In the UFH subgroup, cangrelor reduced the primary composite efficacy end point at 48 hours compared with clopidogrel (4.8% vs 5.9%; odds ratio [OR] 0.80 [0.65 to 0.98]; p = 0.03). Cangrelor consistently reduced ST at 2 hours (0.7% vs 1.3%; OR 0.56 [0.35 to 0.90]; p = 0.01) and 48 hours (0.9% vs 1.4%; OR 0.70 [0.45 to 1.07]; p = 0.10). There was no difference in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-defined severe or life-threatening bleeding (0.1% vs 0.1%; OR 1.24 [0.33 to 4.61]; p = 0.75) or blood transfusion requirement at 48 hours (0.4% vs 0.2%; OR 1.87 [0.83 to 4.21]; p = 0.12). In conclusion, cangrelor reduces early ischemic periprocedural complications without increasing severe bleeding compared with clopidogrel in patients undergoing PCI with UFH.