Immunohistochemistry has rapidly established a significant role in diagnostic pathology. We use immunohistochemistry as an adjunct to morphological diagnosis and employ a "panel approach" to the classification of poorly differentiated tumors. This retrospective analysis was conducted to examine the efficacy of such an approach, using, as an example, the two most common categories of poorly differentiated tumors, namely, the poorly differentiated round cell tumors and spindle cell tumors. Five hundred and fifty-seven consecutive cases of such tumors, collected over a two-yr period, had been subjected to immunohistochemical staining because specific or definitive categorization of the tumor was not possible on the basis of the examination of hematoxylin and eosin stained sections. The clinical history, gross and microscopic findings, as well as the results of immunohistochemical stains were analyzed. Immunohistochemistry allowed a definitive diagnosis to be assigned in 420 cases (75.4%). It was particularly useful in identifying malignant melanoma of both epithelioid and spindle types and distinguished between melanoma, lymphoma and poorly differentiated carcinoma in 126 cases of such lesions occurring in adult lymph nodes. It was also useful in identifying tumors in small biopsies where poor cytomorphological preservation or small size precluded accurate categorization. The application of appropriately chosen panels of antibodies tailored to a narrow list of differential diagnoses helped to identify myogenous, vascular, nerve sheath and fibrocystic lesions among the group of spindle cell tumors. Immunohistochemistry provided definitive diagnoses in 70% of round cell tumors and 92% of spindle cell tumors.(ABSTRACT TRUNCATED AT 250 WORDS)