Objective: To investigate the causes of difficult blood cross-matching and methods of proper blood transfusion and to propose effective managing measures. Methods: From January 2014 to December 2017, 81 patients with difficult blood cross-matching in hospitals in Jiaozuo district were recruited.All the patients were examined before transfusion and analyzed retrospectively and corresponding appropriate management measures were taken. Results: Of the 78 cases of difficult cross-matching blood samples, false coagulation caused by protein turmoil occurred in 4 cases, accoun-ting for 5.1% of the difficult cross-matching specimens, and was managed by adding appropriate amount of normal saline in the procedure cross-matching; 5 cases were with cold autoantibodies, accounting for 6.4% of difficult specimens, and managements was cross-matching under 370 C and transfusing blood under warming condition; 13 cases were with warm autoantibodies, accounting for 16.6% of difficult specimens, management was performing cross-matching after adsorption of the auto-antibody; 56 cases had irregular allotype antibodies detected, accounting for 71.9% of difficult specimens, mana-gement was screening appropriate compatible matching blood for transfusion. Conclusions: The most frequent causes of difficult blood cross-matching are the presence ofirregular alloantibodies and autoantibodies. For avoiding effectively this situation, it is necessary to formulate appropriate transfusion regimen suitable for the patients to ensure the safety and effectiveness of transfusion.