To investigate the potential risk factors for variant Creutzfeldt-Jakob disease (VCJD) in the United Kingdom. Definite and probable vCJD cases (n = 136) were residing in Great Britain at disease onset, and were referred between May 1995 and November 2003. Control subjects (n = 922) were recruited between 2002 and 2003, from 100 randomly selected geographical clusters sampled to represent the geographical distribution of vCJD. Reported frequent consumption of beef and beef products thought likely to contain mechanically recovered or head meat, or both, including burgers and meat pies, was associated with increased risk for vCJD, as was reported frequent chicken consumption. Surgical operations were generally similarly reported for cases and control subjects, with the exception of a small group of minor operations, possibly attributable to underreporting in control subjects. Cases and control subjects had similar reported occupational histories and exposure to animals. These findings are consistent with dietary exposure to contaminated beef products being the main route of infection of vCJD, but recall bias cannot be excluded. There was no convincing evidence of increased risk through medical, surgical, or occupational exposure or exposure to animals.