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Background: Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. Methods: This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. Results: Of 482 randomizations (238 zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. Symptomatic, laboratory-confirmed influenza occurred in 3% of zanamivir subjects and 8% of rimantadine subjects during chemoprophylaxis (P = .038; additional protective efficacy for zanamivir over rimantadine = 61%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. Conclusions: This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly. [Copyright &y& Elsevier]