The influence of family history on DNA repair synthesis, unscheduled DNA synthesis (UDS), was assessed in volunteers with or without a family history of cancer. UDS, following treatment of mononuclear leukocytes with N-acetoxy-2-acetylaminofluorene, was measured as the incorporation of [3H]thymidine into DNA in the presence of hydroxyurea. The positive family history group (n = 71) had an average of 2.4 first-degree relatives with cancer, defined as any major cancer, excluding skin cancer: 31 participants reported that cancer occurred in both their parents. The "no family history' comparison group (n = 29) had no family history of cancer through the second degree. There was a significant reduction in UDS in cells from individuals with family history, compared to those with no family history (P greater than 0.002). This relationship was not explained by factors known to influence UDS, such as age, smoking or hypertension. We conclude that reduced UDS in mononuclear leukocytes is associated with a family history of any major cancer, and is not confined to a history of cancer of any single organ site. This conclusion is further supported by the observation that individuals (n = 13) with parents who had an earlier onset of cancer (less than 60 years) also had a significantly lower DNA repair synthesis than those (n = 18) whose parents had later diagnosis of cancer (greater than 60 years).