Ichthyophthirius multifiliis, causing white spot disease, is a serious pathogen in aquaculture as well as for the ornamental fish industry. In carp, channel catfish and rainbow trout the immune responses against the parasite have been partly elucidated and these species are able to acquire a high level of immunity against the disease. Zebrafish are however, known to be more resilient towards the disease than channel catfish but the pathology and the ability to obtain protection is unknown. In this study a primary infection in the gills of zebrafish was described and the subsequent acquirement of immunity was evaluated. The parasites in the gills induced hyperplasia, an increase of mucus cells, adhesion and shortening of the secondary lamellae, narrowing of water channels and proliferation. The parasite burden was significantly lower in survivor fish and where all naive fish died within 6 days following secondary infection (challenge) only one of the survivor fish died. This study demonstrates that zebrafish are susceptible to I. multifiliis and that gill pathology is similar to the situation observed in rainbow trout. Furthermore, zebrafish are able to acquire immunity against white spot disease and may therefore be a suitable model organism to study innate and protective immunology and host/parasite interactions during I. multifiliis infections.