Loss of body mass, which occurs in the later stages of cystic fibrosis (CF), probably affects all body compartments. We hypothesized that loss of skeletal muscle mass would include inspiratory muscles and impair their function. To test this, we determined the effect of body mass index (BMI) and lean body mass (LBM) depletion on handgrip (HG) force and inspiratory muscle function (IMF). The maximum inspiratory pressure (MIP) and the sustained maximum inspiratory pressure (SMIP) were measured with a computerized system. The relationship of IMF and reduced BMI to survival was studied in 49 patients, and a further 25 patients were studied to define the link between IMF and LBM. LBM was assessed by anthropometry. In the survival study a BMI < 20 kg/m2 was associated with a low SMIP (p < 0.001) and reduced survival, whereas MIP was relatively preserved. In the cross-sectional study SMIP (p < 0.001), MIP (p < 0.01), and HG (p < 0.01) were all reduced in the low LBM group, but not when related to total LBM. C-reactive protein and LBM were inversely related (r = -0.71, p < 0.01). Impaired IMF was chiefly a loss of sustained muscle contraction secondary to a reduced skeletal muscle mass, which may be related to pulmonary inflammation.