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Background: Cold agglutinins are auto-antibodies that can be a nuisance in cross matching and in blood grouping. Here we report an unusual case of a high titer and wide amplitude cold agglutinin reduced by plasmapheresis. Methods and Materials: A 56-year-old man with severe anemia requested a transfusion of red blood cells. However, there was a problem in blood for blood grouping. The discrepancy of blood typing was subsequently resolved using group O absorbed plasma along with repetition of forward grouping with warm-washed red blood cells. The presence of high-thermal-amplitude and a high-titer anti-I cold agglutinin were detected in further serologic investigation. It revealed reactivity against autologous and adult O red blood cells at 37˚C by the thermal amplitude screening test, and demonstrated a very high titer of 65,536 against adult O cells by titration studies at 4˚C. The patient received two plasma exchange sessions of 1.5 plasma volumes each. There was a significant reduction of the titer of cold agglutinins and of the thermal amplitude by plasmapheresis as well (p < 0.01). Results: After successful cross-matching with post plasma exchanges, four units of red blood cells were infused to the patient without any hemolysis symptoms or signs. Conclusions: We now reported a patient with abnormally ascended titer of cold agglutinins and wide-thermal-amplitude, but we also successfully performed ABO typing and cross matching after 2 plasma exchange sessions of 1.5 plasma volumes each.