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To develop time-dependent dose–response models for highly pathogenic avian influenza A (HPAI) of the H5N1 subtype virus.A total of four candidate time-dependent dose–response models were fitted to four survival data sets for animals (mice or ferrets) exposed to graded doses of HPAI H5N1 virus using the maximum-likelihood estimation. A beta-Poisson dose–response model with the N50 parameter modified by an exponential-inverse-power time dependency or an exponential dose–response model with the k parameter modified by an exponential-inverse time dependency provided a statistically adequate fit to the observed survival data.We have successfully developed the time-dependent dose–response models to describe the mortality of animals exposed to an HPAI H5N1 virus. The developed model describes the mortality over time and represents observed experimental responses accurately.This is the first study describing time-dependent dose–response models for HPAI H5N1 virus. The developed models will be a useful tool for estimating the mortality of HPAI H5N1 virus, which may depend on time postexposure, for the preparation of a future influenza pandemic caused by this lethal virus.