The clinical immune and serologieal responses of a flock of 44 sheep which suffered an outbreak of natural orf infection was monitored over a period of one year. Animals were shown to be almost solidly resistant to experimental reinfection of the mouth with a heterologous strain of orf virus up to one year after the outbreak. All animals tested were, however at least partially susceptible to infection of the thigh within one month of recovery from disease. Full susceptibility appeared to be regained within a year. Lambs born to recovered ewes one year after the outbreak were uniformly fully susceptible to experimental mouth infection, but the ewes remained resistant to udder infection while nursing the infected lambs. Most, but not all, sheep developed precipitating antibodies in association with the outbreak of disease. An antigen of high potency was required to detect such antibodiea, the presence of which fluctuated in individual animals during the monitoring period. Results also varied with the use of antigens prepared from different strains of orf or milker's nodule virus. Using a plaque-reduction assay, some sheep were found to develop low levels of serum neutralising antibodies, either in association with the outbreak of disease or following experimental reinfection. There was no correlation between the severity of clinical lesions and susceptibility to subsequent challenge infection of mouth or thigh and the development of precipitating or serum neutralising antibodies. Precipitating and serum neutralizing antibodies also appeared to develop independently of each other and were not passively transferred from ewe to lamb to any significant extant. Sheep vaccinated by thigh scarification were in most cases susceptible to reinfection within one month. Precipitating and serum neutralizing antibodies were detected after one or two revaccinations. In agar-gel diffusion tests, five strains of orf virus appeared antigenically identical. Orf and milker's nodule viruses were similarly indistinguishable and both were very closely related to bovine popular stomatitis virus.