The induction of foot-rot when Fusiformis nodosus was applied to the macerated feet of sheep, was found to require a factor present in faeces. The infection was not associated with any detectable invasion by Strongyloides papillosus larvae. When there was faecal contamination the interdigital stratum corneum was usually colonized by Fusiformis necrophorus, suggesting that F. necrophorus is the required factor. This was supported by the finding that intracutaneously injected F. nodosus did not induce foot-rot in clean feet unless F. necrophorus was present. The highest incidence resulted when the inoculum also included Corynebacterium pyogenes, which produces a factor that increases the growth and invasiveness of F. necrophorus. F. nodosus is excluded from the dermis by the presence of phagocytes and a humoral bactericidal system. There is no evidence that its growth in the epidermis is subject to phagocytosis or assisted by the leucocidal action of F. necrophorus. F. necrophorus appears to contribute to the pathogenesis of foot-rot through (i) its early superficial invasion, and the resulting midl epidermal damage which evidently assists the establishment of F. nodosus, and (ii) a deeper, more destructive invasion of the tissues by F. necrophorus once F. nodosus is established. F. nodosus has little inflammatory or destructive action, but possesses three properties that are probably essential to the disease process. (1) It is the only organism able to initiate the bacterial invasion of the epidermal matrix of the hoof: this ability is associated with high protease production. (2) F. nodosus has an unusual capacity for slow persistent growth in vitro in the presence of limited nutrients: this is associated with the ability to persist in the lesion and to sustain the infection between the intense but brief waves of growth of F. necrophorus. (3) F. nodosus produces a heat-stable soluble factor that increases the growth of F. necrophorus in vitro and its infectivity and invasiveness in vivo. It is concluded that foot-rot is caused by the association of F. nodosus, the transmitting agent, with F. necrophorus, a normal inhabitant of the ovine environment. The association is synergic, each organism contributing directly to the pathogenic process while assisting the other to grow in the infected tissues. The initial establishment of these two fastidious anaerobes is probably facilitated by the metabolism of C. pyogenes and other aerobic diphtheroid bacteria found at the surface of the lesion. © 1968.