Background: No previous study has assessed the possible role of dipyridamole for treatment of no‐reflow during acute myocardial infarction (AMI). Methods and Results: Forty‐six consecutive patients (age 64 ± 13 years, 37 men) with no reflow during primary percutaneous coronary intervention were randomized to initial treatment with either dipyridamole (0.56 mg/kg i.c.) or verapamil (1 mg i.c.). Patients with unsuccessful response to the first drug were then switched to the second one (from dipyridamole to verapamil and vice versa). Angiographic end‐points were similar in the two groups: TIMI flow was 2.9 ± 0.3 versus 2.8 ± 0.4 (P = 0.28), corrected TIMI frame count (cTFC) 26.4 ± 8.8 versus 31.6 ± 11.4 (P = 0.14) and TIMI myocardial perfusion grade (TMPG) 2.1 ± 1.2 versus 1.7 ± 1.2 (P = 0.12) in dipydidamole and verapamil group, respectively. Optimal myocardial perfusion (TMPG‐3) was achieved by 56% of patients with dipyridamole and 39% with verapamil (P = 0.38). In patients with persistent no‐reflow administration of dipyridamole on top of verapamil resulted in a significant further improvement of cTFC (from 31.6 ± 11.4 to 24.6 ±5.7 P = 0.009) and of TMPG (from 1.7 ± 1.2 to 2.6 ± 0.7, P = 0.007). Conversely, verapamil did not induce a significant improvement in coronary flow (cTFC changed from 26.4 ± 8.8 to 24.5 ± 8.5, P = 0.28 and TMPG from 2.1 ± 1.2 to 2.4 ± 1.2, P = 0.13). There were no significant side effects induced by dipyridamole, while verapamil caused AV block in 9% of cases. Conclusions: Dipyridamole is a safe and effective first‐line drug for treatment of no‐reflow. Dipyridamole can also be successfully used in patients with incomplete response to verapamil. © 2010 Wiley‐Liss, Inc.