To assess the serum immune response in infants with gastroenteritis caused by human calicivirus (HCV), we tested a total of 165 serum specimens for antibodies to HCV by a radioimmunoassay blocking (RIA-BL) test. The specificity of the RIA-BL test for antibody to HCV was established as follows: paired sera from patients with HCV gastroenteritis revealed significant rises in antibody to HCV, whereas there was no significant change in RIA-BL titer to HCV in paired sera collected from the same individuals when infected with other gastroenteritis viruses. We analyzed 41 paired sera from patients and from healthy contacts involved in an outbreak of HCV gastroenteritis. All 23 infants without preexisting antibody revealed a sharp rise in HCV titer, and 18 (73%) of 23 of them developed illness. Fifteen of 18 infants with preexisting antibody also revealed a significant rise in HCV antibody, but only 3 (16.7%) of 18 became ill (P less than .01). These data suggest that the presence of serum antibody may correlate with resistance to illness in HCV gastroenteritis.