Despite the wide use of the antibody detection test for unexpected antibodies, controversy still remains regarding the use of enzyme-treated red blood cells. Over a 6-year period, 72,573 samples from 49,863 patients submitted for pretransfusion compatibility testing were examined for unexpected antibodies. The antibody detection tests included a low-ionic-strength solution (LISS) indirect antiglobulin test and a two-stage papain (2SP) test. One thousand and seventy of the 2267 (47%) antibodies tested by 2SP were reactive only by the 2SP test. Overall, the 2SP test detected only 0.6% of antibodies considered to be clinically significant (10 examples of anti-c and 2 examples of anti-e). The slight additional safety provided by detection of clinically-significant antibodies is overshadowed by the high number of clinically-insignificant antibodies detected by the 2SP test.