Lymphocytes with natural killer (NK) ability recognize a wide range of target cells; however, the mediators of specific target recognition are still largely unknown. Despite the diversity of the NK target repertoire, it is typified by cells of relatively immature phenotype. The purpose of this study was to determine if colorectal carcinoma (CRC) targets were sensitive to spontaneous lysis by fresh human NK effector cells and to observe the role of CRC differentiation in this process. Results demonstrated that poorly differentiated CRC targets were susceptible to NK-mediated lysis whereas CRC targets with more differentiated structure were NK resistant. In addition, chemical induction of a more mature CRC phenotype confers NK resistance on a previously NK-susceptible target. This maturation-related modulation of NK sensitivity can provide a model with which to further study interaction between NK cells and CRC targets.