Inherited deficiency of complement C3 has been described in guinea pigs, dogs and 20 humans. Homozygous deficiency of C3 is associated with recurrent pyogenic infections by encapsulated bacteria, especially H. influenzae, S. pneumoniae and N. meningitidis. In dogs and humans there is also an association with development of glomerulonephritis of the mesangiocapillary type. Some patients also develop transient erythematous rashes in association with pyogenic infections, with histology showing predominantly neutrophil infiltration and small vessel vasculitis. Studies of antibody responses, mainly in experimental animals have shown impaired primary and secondary responses to both thymus-dependent and -independent antigens at low immunizing doses, with a reduced switch from IgM to IgG production. The molecular basis of C3 deficiency has been established in two humans with C3 deficiency. In one it was due to a splice junction mutation and in another, to a partial gene deletion. These mutations are not compatible with the production of functional C3 in any tissue. Such patients with absolute C3 deficiency are a valid model for understanding the physiological role of C3 in vivo.