Epidemiologic studies have established a strong association between cigarette smoking and lung cancer, but the risk estimates for women are less impressive than for men. We assessed the possible role of family history and its interrelationship with cigarette smoking as risk factors for lung cancer in women by conducting a case-control study. Among 112 cases, 7% had a primary family member with lung cancer compared with only 3% of 224 controls for an odds ratio of 2.8. Cigarette smoking was present for 87% of the cases and 41% of the controls for an odds ratio of 11.3. The ecogenetic interrelationship of cigarette smoking and family history was supported by the gradient in the odds ratio for lung cancer created by the two variables: patients who never smoked but had a positive family history had an odds ratio of 5.7; patients who smoked but had a negative family history had an odds ratio of 15.1; and patients who smoked and had a positive family history had an odds ratio of almost 30. We conclude that family history may be an important risk factor for lung cancer in women, and that the ecogenetic interrelationship of family history with cigarette smoking may help explain the occurrence of this disease in women.