The role of both primary and secondary cigarette smoke exposure in the causation of lung cancer appears certain. An estimated 90% of lung cancer is attributed to cigarette smoke. Remarkably, however, less then 20% of cigarette smokers develop lung cancer. Investigators have suggested that a genetic predisposition to lung cancer may contribute to familial aggregation of this cancer. To understand the contribution of familial aggregation to this type of cancer and potentially identify individuals and families, which may be important in identifying gene(s) responsible for lung cancer, we developed criteria for identification of high-risk families. We have tested the feasibility and utility of these criteria at three Denver, CO hospitals with very different patient populations. Four hundred eighteen individuals were diagnosed with lung cancer at these three hospitals between 1/1/95 and 8/31/95. Twenty-nine percent of individuals expired prior to the time of initial contact. Family history data were obtained on 182 individuals. To be considered positive (suggesting possible autosomal dominant inheritance of lung cancer), families must have at least two first-degree relatives with lung cancer, one of which must be diagnosed before the age of 55. Seventeen of 182 (9.3%) families in the study population met these criteria. We reviewed the remaining family histories that did not meet the established criteria and identified another 2.3% (5/182) of families had evidence for autosomal dominant transmission of lung cancer. An additional 15% (23/182) of families had histories which could not be classified without further information. This study suggests that at least 11.6% of individuals diagnosed with lung cancer will have a positive family history of lung cancer. Use of the criteria developed for this study may lead to an underestimation of the inherited etiology of lung cancer.