BACKGROUND: Both adverse early life exposures and adult smoking can negatively influence adult lung function trajectory but few studies consider how the impact of early life exposures may be modified by subsequent smoking. METHODS: The Medical Research Council National Survey of Health and Development is a nationally representative cohort, initially of 5362 individuals, followed since enrolment at birth in March 1946. Using data collected prospectively across life and multilevel modelling we investigated how the relationships between early life exposures (infant lower respiratory infection, manual social class, home overcrowding and pollution exposure) and FEV1 and FVC trajectories between ages 43 and 60-64 were influenced by smoking behaviour. RESULTS: Among 2172 individuals, there were synergistic interactions of smoking with infant respiratory infection (P=0.04) and early life home overcrowding (P=0.009), for FEV1 at 43 years. Within smoker-stratified models, there were FEV1 deficits among ever-smokers associated with infant lower respiratory infection (-108.2ml; P=0.001) and home overcrowding (-89.2ml; P=0.002) which were not evident among never-smokers (-15.9ml; P=0.69 and -13.7ml; P=0.70 respectively). FVC modelling, including 1960 individuals, yielded similar results. FEV1 decline was greater in smokers (P<0.001) but there was no effect of any early life exposure on FEV1 decline. Neither smoking nor early life exposures were associated with FVC decline. CONCLUSIONS: Besides accelerating adult FEV1 decline, cigarette smoking also modifies how early life exposures impact upon both mid-life FEV1 and FVC. These findings are consistent with smoking impairing pulmonary development during adolescence or early adulthood thereby preventing catch-up from earlier acquired deficits.