Human epidemiology studies demonstrate an inverse correlation between serum levels of vitamin A and the incidence of lung cancer. While such studies suggest that vitamin A may have a role in cancer prevention, the intent of this study was to investigate the use of vitamin A status parameters as markers for detection of occult lung cancer. In the first of two phases of this study, we established criteria for a prospective screening study. Serum levels of retinol-binding protein (RBP), zinc, retinol, and beta-carotene in lung cancer patients were compared to levels in controls. For the second phase, a prospective screening study, 100 ambulatory male cigarette smokers over the age of 45 were enrolled. Subjects were excluded if they had a known diagnosis of cancer, recent weight loss, or serum albumin less than 3.5 g/dl. Subjects with RBP less than 4.2 mg/dl and retinol less than 42 micrograms/dl were classified as high-risk; those remaining were classified as controls. A chest X-ray (CXR) was obtained on all 17 high-risk subjects and on 26 of the 83 controls. CXR was read and follow-up was performed by physicians without knowledge of this study. Lung cancer was detected in 24% (4/17) of the high-risk subset, and 4% (1/26) of the controls. These data suggest that retinol and RBP may be useful in lung cancer screening for selecting a high-risk population that warrants further examination.