A differentiated cell expressed an entire set of specialized features. Somatic cell hybridization provides a method to examine control of gene regulation. The expression of tissue-specific features was studied in hybrids between human promyelocytes (HL-60) and human Burkitt''s lymphoma cells (P3HR-1). Two hybrid lines, HP-1 and HP-2, and 18 hybrid clones were established and confirmed by karyotype, isozyme and surface antigen analyses. The hybrids lacked the 10 myeloid (HL-60) features that were examined including myeloid morphology, histochemistry and functions that included response to colony-stimulating factor and ability to differentiate to granulocytes or macrophages. The hybrids synthesized Ig and expressed Epstein-Barr nuclear, early and viral capsid antigens similar to the P3HR-1 lymphoid parental line. Results are contrasted to the findings when P3HR-1 lymphocytes are fused to human erythroid-myeloid cells (K562). Phenotypic differences between human myeloid and lymphoid cells in the hematopoietic lineage may involve mutually exclusive programs and may possibly be mediated by the activity of diffusible, transacting molecules.