Annual decline in lung function determined longitudinally is often compared with predicted decline determined cross-sectionally. To test this comparison, spirometric data were collected 5 times over 5 yr from 52 adult male Caucasians. The age regression coefficient for FEV1 and FVC, determined cross-sectionally at each visit, was more than twice the longitudinal annual change computed from the same data as the mean of the slopes of each subject's regression lines. The discrepancy persisted even when the first visit was deleted to reduce learning effects on longitudinal estimates. This discrepancy may be partly explained by the sensitivity of cross-sectional analyses to past noxious influences, whereas longitudinal analyses are sensitive only to influences that continue to affect annual decline during the study period. We also found historical evidence of an increase in height-specific VC, which would artifactually steepen cross-sectionally determined regression lines. Thus, observed longitudinal changes of study cohorts should be compared with control longitudinal data.