Context: Influenza virus is a major cause of illness, disruption to daily life, and increased use of health care in all age groups. Objective: To assess the safety and effectiveness of intranasally administered trivalent, live, attenuated influenza virus (LAIV) vaccine for reducing illness, absenteeism, and health care use among healthy, working adults. Design: Randomized, double-blind, placebo-controlled trial conducted from September 1997 through March 1998. Setting: Thirteen centers across the United States. Participants: A total of 4561 healthy, working adults aged 18 to 64 years recruited through health insurance plans, at work sites, and from the general population. Intervention: Participants were randomized 2:1 to receive intranasally administered trivalent LAIV vaccine (n = 3041) or placebo (n = 1520) in the fall of 1997. Main Outcome Measures: Episodes of febrile illness, severe febrile illness, febrile upper respiratory tract illness, work loss, and health care use during the peak and total influenza outbreak periods, and adverse events. Results: Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods (13.2% for vaccine vs 14.6% for placebo; P = .19). However, vaccination significantly reduced the numbers of severe febrile illnesses (18.8% reduction; 95% confidence interval [CI], 7.4%-28.8%) and febrile upper respiratory tract illnesses (23.6% reduction; 95% CI, 12.7%33.2%). Vaccination also led to fewer days of illness across all illness syndromes (22.9% reduction for febrile illnesses; 27.3% reduction for severe febrile illnesses), fewer days of work lost (17.9% reduction for severe febrile illnesses; 28.4% reduction for febrile upper respiratory tract illnesses), and fewer days with health care provider visits (24.8% reduction for severe febrile illnesses; 40.9% reduction for febrile upper respiratory tract illnesses). Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes. Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination, but serious adverse events between the groups were not significantly different. The match between the type A(H3N2) vaccine strain and the predominant circulating virus strain (A/Sydney/05/97[H3N2]) for the 1997-1998 season was poor, suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain. Conclusion: Intranasal trivalent LAIV vaccine was safe and effective in healthy, working adults in a year in which a drifted influenza A virus predominated.