Prior studies have suggested that lung cancers that arise in association with cigarette smoking favor an upper-lobe location while those associated with asbestos exposure favor a lower-lobe location. An excess of adenocarcinomas has also been reported among cases not exposed to cigarette smoke as well as among those exposed to asbestos. However, these studies typically have not adjusted adequately for potential confounders such as the patient's age, sex, race, or family history of cancer. To better examine the effects of cigarette smoking and asbestos exposure on location and histology of lung cancer, we analyzed data from a large case-control study that included 456 patients with stage I or II lung cancer. Patients with upper-lobe tumors tended to have had more exposure to tobacco as assessed by pack-years smoked (54.7 versus 46.2, p = 0.07) and less time since quitting smoking (3.0 versus 5.5 yr, p = 0.05). In contrast to some prior reports, asbestos exposure was also associated with an upper-lobe location of tumor. Among those with upper-lobe tumors, 14.6% had a history of significant asbestos exposure compared with 5.4% of those with lower-lobe tumors (p < 0.01). The relationship between asbestos exposure and upper-lobe location of tumor was also statistically significant whether stratified by smoking or analyzed by multivariable logistic regression modeling. Adenocarcinomas were more likely among those with less exposure to cigarette smoke based on fewer pack-years smoked (41.5 versus 61.8, p = 0.0001) and more time since quitting smoking (5.0 versus 3.0 yr, p = 0.02). The proportion of patients with significant exposure to asbestos was lower among those with adenocarcinomas but was not statistically significant (9.5 versus 15.3%, p = 0.09). In multivariable logistic regression analysis, longer time since smoking exposure remained a significant predictor of adenocarcinomas (p < 0.02), but history of asbestos exposure did not predict tumor histology. Thus, in patients with lung cancer, both cigarette smoking and asbestos exposure histories favor an upper-lobe location of tumor. Longer time since smoking exposure favors adenocarcinomas, but the history of asbestos exposure does not appear to influence the tumor histology.