Tenacious airway secretions are responsible for much of the lung damage in cystic fibrosis (CF). Label warnings on potential secondary effects of some antihistamines include possible drying or thickening of lower airway secretions, suggesting that they are detrimental to individuals with airway disease. We studied the effects of cyproheptadine hydrochloride (CH) on sputum weight, viscoelasticity, and transportability in CF patients participating in a pilot trial of CH as an appetite stimulant to assure no potential adverse secondary effects on mucus clearance. Sixteen clinically stable subjects were randomized to receive either CH (2 mg QID for 1 week followed by 4 mg QID for 11 weeks) or placebo. Sputum was obtained by voluntary forced cough and expectoration prior to starting CH or placebo and at 4 weeks. Viscoelasticity was measured by rheometry and cough transportability by simulated cough machine. Sufficient paired sputum for rheologic analysis was obtained on four placebo and seven CH subjects and for cough transportability analysis on three placebo and six CH subjects. Weight on all specimens was obtained prior to both analyses. There were no significant differences in sputum weight wet, measures of mucus viscoelasticity (rheology), or cough transportability of mucus between baseline and 4 weeks in patients on placebo or CH. From this limited study, CH, a first-generation antihistamine, appears to have no adverse effects in sputum viscoelasticity or cough transportability in CF patients.