Cystic fibrosis (CF) is characterised by inspissated airway secretions and chronic endobronchial infection associated with exuberant neutrophilic inflammation. Unfractionated heparin may be mucolytic and has demonstrated a number of anti-inflammatory properties; however, further safety data are needed in these subjects who are at risk of airway bleeding. The current study aimed to assess the medium-term safety and tolerability of moderately high-dose inhaled heparin in CF adults and to explore possible in vivo mucolytic and anti-inflammatory outcomes. A randomised, double-blind, placebo-controlled crossover study of twice daily inhalation of 50,000 IU of heparin for 2 weeks was undertaken in CF adults, with a 1-week washout period. Eighteen subjects were randomised and 14 (mean+/-sd age 23+/-7.8 yrs and percentage-predicted forced expiratory volume in one second 52.1+/-15.56%) completed the study protocol. Heparin neither affected blood coagulation parameters nor resulted in any increase in adverse events. Heparin inhalation had no significant effect upon forced expiratory volume in one second, symptoms of sputum clearance or sputum inflammatory markers. The current pilot study demonstrated no evidence of improved sputum clearance with 50,000 IU of inhaled heparin given twice daily to adult cystic fibrosis subjects. However, inhaled heparin was safe and the future evaluation of larger doses over a longer period may be warranted.