Hyperimmunized bovine plasma containing antibodies to a mutant Escherichia coli O111:B4 (J5) was used to conduct a prospective double-blind clinical trial to evaluate its efficacy as an immunotherapy to bovine neonates in field conditions. Two- to three-day-old calves (N = 150) were randomized into three groups (n = 50) to receive (1) no plasma (NP) or (2) control (traces or no J5 antibody) bovine plasma (CP), or (3) hyperimmune bovine anti J5 plasma (HP) in two subcutaneous total doses of 10 ml kg-1 body weight at a 24 h interval. Various physiological, pathological and clinical parameters of the study subjects were observed up to three weeks while other data such as morbidity, mortality and the effect on heart girth increase were collected up to the end of the eighth week. Weekly serum total protein and immunoglobulin G (IgG) concentrations were preferentially increased from the baseline values in HP calves but not statistically significant (p > 0.05) in group comparison. Mean (geometric) serum J5 ELISA titers in the HP group were significantly (p < 0.001) higher than the other two groups that increased about 1-log by the first week of plasma intervention, followed by a gradual decline by the third week. Out of three total deaths due to septicemia and colitis, one was from the NP group while the other two were from the HP group. Morbidity as measured daily on a 13-point scoring scale were not statistically (p > 0.05) different among the groups. Variation in the mean heart-girth increase was non-significant (p > 0.05) among groups by the eighth week. Higher increase in heart girth was generally associated with higher initial serum IgG (p < 0.01) concentration. Our results suggest that this lot of hyperimmune J5 plasma at this dose was not superior to control plasma or to no intervention in terms of calf morbidity and mortality.