The ability of UV light, mitomycin C and ionizing radiation to induce the formation of sister chromatid exchanges (SCEs) at the same locus in successive cell generations was investigated in human lymphocytes. Cells were exposed to the DNA damaging agents after they had completed their first round of DNA replication, and SCEs were examined at the third division in chromosomes that had been differentially stained three ways. Although some of these treatments induced long-lived lesions that increased the frequency of SCEs in successive cell generations, none of the lesions led to the formation of consecutive SCEs at the same locus in successive cell generations. This observation seriously challenges the hypothesis that SCE cancellation results as a consequence of persistence of the lesions induced by these agents.