Evidence for a relationship between nutritional growth retardation in cystic fibrosis (CF) and progressive pulmonary dysfunction was evaluated by a prospective longitudinal study of changes in nutritional growth parameters, in relation to changes in pulmonary function data, in 61 moderately affected CF patients, aged 5-17 yr, during the equilibrated phase of lung growth. Age, sex, initial and serial weight and height Z scores, body cell mass (BCM) by total-body potassium (TBK) analysis, and changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), excluding data during pulmonary exacerbations, were analyzed by multiple regression analyses. The only significant predictor of change in FVC (best-fit model) was change in BCM, expressed as TBK (g/yr), TBK for age (percentage predicted), and TBK for height (percentage predicted) (p < 0.01). Standard anthropometric variables were not predictive. No reliable predictive model emerged for changes in FEV1. Relative decline in TBK for age was strongly predictive of decline in FVC (percentage predicted) accounting for 23% of this change. Patients with normal growth of the BCM had significantly less decline in FVC than those with retarded growth of the BCM (a fall of 2.5 vs. 6.8%/yr, p < 0.01). Impaired growth of the metabolically active BCM appears to be associated with progressive lung dysfunction in CF, possibly mediated by impaired lung growth. Achieving optimal nutrition and growth may minimize the progressive decline in pulmonary function commonly seen in this disease.