Prior studies have found cross-sectional lung function to be highly heritable. In the present study, we used a 10-cM genome-wide scan of 1,578 members of 330 families participating in the Framingham Study to test for linkage of genetic markers to level of lung function as determined by spirometry during middle age. At this age, lung function measures may reflect the effects of genes influencing lung growth and development, as well as of those influencing decline in lung function during adulthood. We performed spirometry on 345 members of the Original Cohort and 1,233 members of the Offspring Cohort of the Framingham Study. The effects of age, height, body mass index, and smoking status on spirometric measures were adjusted through linear regression models created separately for men and women in each cohort. Standardized residuals for FEV1, FVC, and the ratio of FEV1 to FVC were obtained from these models. The residual spirometric measures were analyzed for linkage to the genome scan markers through the use of variance component models in the Sequential Oligogenic Linkage Analysis Routines software program. The loci most strongly influencing FEV1 and FVC colocalized on chromosomes 4, 6, and 21. FEV1 was most influenced by the locus on chromosome 6 (logarithm of the odds favoring genetic linkage [LOD] = 2.4), whereas chromosome 21 contained markers with the strongest linkage to FVC (LOD = 2.6).