The effect of the neuraminidase inhibitors zanamivir and oseltamivir on the transmission of highly pathogenic avian influenza (HPAI) in chickens was studied. Per group, five chickens inoculated with HPAI A/Chicken/Pennsylvania/1370/83 H5N2 virus were placed 1 day post-inoculation (p.i.) in one cage with five contact chickens. Inoculated and contact chickens were treated twice daily from 1 day before inoculation up to day 7 p.i. All untreated inoculated and contact chickens became infected and four inoculated and two contact chickens died. Similarly, all of the zanamivir-treated inoculated and contact chickens became infected and all inoculated and four contact chickens died. Obviously, locally active zanamivir has no effect. In contrast, although oseltamivir could not prevent tracheal infection of the inoculated chickens, none had an infected cloaca and only one died. More important, only after stopping treatment three contact chickens became positive, suggesting limited transmission within or after the treatment period. In conclusion, treatment with systemically active oseltamivir limits to a large extent a severe outcome and chicken-to-chicken transmission of HPAI virus.