Appetite stimulants have been used to help overcome decreased appetite and malnutrition in children and adults with various chronic illnesses, including cystic fibrosis (CF). Stimulants have included megestrol acetate (MA), cyproheptadine hydrochloride (CH), cannabinoids, hydrazine sulfate, anabolic hormones, and growth hormone. Many of these, including MA, have substantial side effects and may not be suitable for prolonged use. We previously studied the effects of CH on weight gain in a short-term (12 week) trial in CF with good results compared to placebo. Side effects were few, and weight gain was significant. In this study, we sought to determine the effects of CH over a longer term in order to assess its suitability for prolonged use. Sixteen CF children and adults enrolled in the original short-term study subsequently entered this study, and 12 completed the 9-month trial. All patients receiving placebo in the original short-term study received CH 4 mg up to four times a day in the long-term study continuation, and those receiving CH in the short-term study continued on the drug. No pill counts were done, and patients were queried at quarterly visits as to their CH use. Anthropometrics and spirometry were also done quarterly, and antibiotic use was quantified. Subjects who had changed from placebo (CH2 group) gained weight significantly over 3–6 months, and those continuing on CH (CH1 group) generally maintained previously gained weight over the duration of the study. Select spirometric measures improved in both groups but not significantly, and side effects were mild. CH appears to be an effective appetite stimulant in CF, and generally maintains its effect over time with an acceptable side-effect profile. Pediatr Pulmonol. © 2005 Wiley-Liss, Inc.