Inoculation of lambs with a New Zealand strain of orf virus (NZ 2) failed to protect them against subsequent infection with the Lister strain of vaccinia virus. Similarly, in the reciprocal test, vaccinia virus failed to protect against subsequent orf virus infection. Inoculation with either orf virus or vaccinia virus alone afforded protection against reinfection with the same virus. These results have relevance to the use of vaccinia virus gene vectors in sheep.