We previously found that 40% of breast cancer patients showed enhanced sensitivity to X-ray induced chromosome damage in G 2 lymphocytes and suggested that this might indicate a low penetrance predisposition to breast cancer, for which there is good epidemiological evidence. We have now tested the hypothesis that elevated G 2 radiosensitivity is a marker of such predisposition to other common cancers. We tested patients with colorectal cancer, for which there is also good epidemiological evidence of inherited risk in a substantial proportion of cases, and patients with cancers having a strong environmental aetiology (lung and cervix). We also repeated our study of breast cancer cases and tested patients with chronic diseases other than cancer. The results support our hypothesis, in that 30% (12/37) of colorectal cases showed enhanced sensitivity compared with 9% (6/66) of normal healthy controls (P = 0.01), whereas the proportions of sensitive cervix (11%, 3/27, P = 0.72) and lung cancer cases (23%, 8/35, P = 0.07) were not significantly above normals. We confirmed the enhanced sensitivity of 40% (12/31, P = 0.001) of breast cancer patients and found that patients with non-malignant disease had a normal response in the assay (12%, 4/34, P = 0.73). We suggest that enhanced G 2 chromosomal radiosensitivity is a consequence of inherited defects in the ability of cells to process DNA damage from endogenous or exogenous sources, of a type that is mimicked by ionizing radiation, and that such defects predispose to breast and colorectal cancer. © 2001 Cancer Research Campaign.