The aim of the present study was to investigate Proteus vulgaris infections in Nile tilapia,and red swamp crayfish and homologous and heterologous-species susceptibility of both Nile tilapia and Red swamp crayfish. Eight isolates of suspected Proteus vulgaris were recovered from 6 fish out of 50 Nile tilapia collected from fish pond in Assiut Governorate. While, 12 isolates were recovered from 12 red swamp crayfish. Suspected isolates were identified as P. vulgaris.The pathogenicity of P. vulgaris to Nile tilapia and red swamp crayfish were experimentallly studied and revealed that an increase in the susceptibility to infection was observed in Nile tilapia experimentally infected with the P.vulgaris isolated from fish when compared to those infected with a strain isolated from red swamp crayfish. The mortality rates were 53.33and 33.33% respectively, by the end of the challenge. Equivalent experiments demonstrated that P.vulgaris isolated from the Nile tilapia was more virulente to red swamp crayfish than that isolated from crayfish. The mortality rates were 66.67% and 33.3%   respectively.