Strains of human coronavirus (HCV) isolated between 1974 and 1976 have been studied in vitro and in volunteers. All strains caused colds in volunteers, and those cultivable in tissue culture (TC) produced significantly more coryza and less sore throat than strains growing only in organ culture (OC). The TC strains were serologically related to 229E, but these isolates produced colds with a frequency and severity that contrasted with the effects of 229E itself. Tests on volunteers' preinfection sera showed that the prevalence of antibody to 229E had increased during the period 1961-1979 and that during 1977-1979 only 11% of subjects had no neutralising antibody against 229E. Susceptibility to the 229E-related isolates PR and TO was associated with low preinfection serum neutralising antibody against the homologous virus, and paired sera frequently showed fourfold or greater antibody rises, most commonly against the homologous strain. Volunteers infected with TO were immune when reinoculated with the same strain approximately 1 year later, but other similar volunteers were at least partly susceptible to infection with a heterologous 229E-related virus after similar time intervals. Although the strains of HCV that were grown in tissue culture were all related to the prototype 229E, they appeared not to be identical with it, and this heterogeneity is probably a significant factor in the epidemiology of HCV infections.