Interphase cytogenetics has been used to detect tumor cells in the presence of a large excess of normal cells. Probes for fluorescence in situ hybridization were chosen to reveal a specific hybridization pattern in tumor cell nuclei as well as to provide an internal control for the assessment of the hybridization results. By enumerating mixtures of cytogenetically normal cells and tumor cells from a Burkitt lymphoma cell line, we were able to detect tumor cells at a frequency of one in 500. Normal cells could be differentiated from Burkitt lymphoma cells with a specificity of approximately 99.9%.