Cystic fibrosis (CF) is characterized by malnutrition, chronic pulmonary inflammation, and oxidative stress. Whey protein is rich in sulfhydryl groups and is recognized for its ability to increase glutathione and reduce oxidative stress. Previously, we have shown that supplementation with whey increased intracellular glutathione levels in patients with CF. We have subsequently shown that hyperbaric pressure treatment of whey protein promotes the release of novel peptides for absorption, increases intracellular glutathione in healthy subjects, and reduces in vitro production of interleukin (IL)-8. We hypothesized that pressurized whey supplementation in children and adults with CF could have significant nutritional and anti-inflammatory benefits. A pilot open-label study of 1-month dietary supplementation with pressurized whey in CF patients was undertaken to assess the effects. Twenty-seven patients with CF (nine children, 18 adults) were enrolled. The dose of pressurized whey was 20 g/day in patients less than 18 years of age and 40 g/day in older patients. Anthropometric measures, pulmonary function, serum C-reactive protein (CRP), whole blood glutathione, and whole blood IL-8 and IL-6 responses to phytohemagglutinin (PHA) stimulation were measured at baseline and at 1 month. Three adults withdrew (one with gastrointestinal side effects, two with acute infection). Both children and adults showed enhancements in nutritional status, as assessed by body mass index. Children showed improvement in lung function (forced expiratory volume in 1 second). The majority of patients with an initially elevated CRP showed a decrease. PHA-stimulated IL-8 responses tended to decrease in the adults. Whole blood glutathione levels did not change. Thus, oral supplementation with pressurized whey improves nutritional status and can have additional beneficial effects on inflammation in patients with CF.