The rheology of spontaneously expectorated sputum from CF and COPD subjects and induced sputum from normal controls was characterised by dynamic oscillatory rheometry to validate a method using homogenised specimens. Whole, homogenised specimens showed acceptable reproducibility at different volumes while non-homogenised aliquots from the same samples showed substantial heterogeneity. The viscoelasticity of CF sputum was significantly greater than both COPD and normal sputum, however differences disappeared after stratification of samples by sputum purulence. While mucoid CF sputum did not differ from normal, mucoid COPD sputum had significantly greater elasticity than both mucoid CF and normal samples. Double-blind, randomised, placebo-controlled crossover studies of two weeks of twice daily inhalation of 50,000 IU of heparin were undertaken in adult CF and COPD subjects. Heparin inhalation was safe, however there were no improvements in air inflammation, sputum rheology or clinical outcomes in CF or COPD subjects. The failure of in vitro anti-inflammatory effects of heparin to translate into clinical efficacy may relate to no-specific protein binding within the airways in conjunction with obstruction to drug delivery by secretions and airway obstruction. Additionally, both the dose of heparin and the trial duration may have been insufficient to influence airway inflammation and effect improvements in airway calibre. A longer period of heparin inhalation in subjects with mild lung disease may be effective. Furthermore, measurements of inflammation and mucus rheology in spontaneously expectorated sputum showed substantial variability. The reliable clinical assessment of these outcome measures therefore requires new strategies, possibly by using induced instead of spontaneously expectorated sputum.