We have investigated the action of trypsin treatment on formalin-fixed, paraffin-embedded tissue sections prior to immunostaining with a variety of commercially available poly- and monoclonal antibodies commonly used in surgical pathology. Although enzymatic predigestion often markedly reduced the background and enhanced the immunoreaction for certain antibodies, false negative staining or no enhancement of the staining was observed with other antibodies. We conclude that the indiscriminate practice of trypsinization in immunohistochemical procedures could be a significant cause of false negative results and of discrepancies between laboratories. Therefore, each laboratory must develop its own quality control program for variables such as enzymatic predigestion.