Forty-one cystic fibrosis (CF) patients and 89 family members were immunized in a double-blind randomized 3-year trial with either intranasal live cold-adapted (ca) influenza A vaccine or the recommended intramuscular trivalent inactivated (triv) influenza vaccine. Local, respiratory, and systemic symptoms after vaccine were infrequent and did not differ between vaccine groups. CF patients did not differ from family members in immune response to either vaccine. Although antibody responses tended to be higher after triv vaccine, > or = 85% of subjects had mean hemagglutination inhibition antibody titers > or = 1:32 to influenza H1N1 and H3N2 after the first dose of either vaccine. Infection with influenza H3N2 viruses circulating during this study occurred with comparable low frequency in CF patients after ca (14 infections/100 subject-years of observation) or triv vaccine (10 infections/100 subject-years of observation). Influenza A ca vaccines appear to be safe, immunogenic alternatives to influenza A inactivated vaccines for CF patients and their families.