Background: Among blood groups of red blood system, ABO blood group is requirement for blood transfusion in Viet Nam. Methods: ABO group is determined by 2 methods: serology test to determine antigens on surface of red blood cells and red blood cells test to determine antibodies in serum. In some cases, the result from two this methods are not matched. Results: A study on 101 defined difficult cases during 04/2009-04/2012 at Cho Ray Hospital is shown that to meet with serious difficulties of 52 cases by serum test, and 56 cases to define by red blood cells test, both of 42 cases. Conclusion: Solution to solve the difficulties to safe blood transfusion.