SummaryA heterophile rheumatoid factor (RF) response to LPS was measured in mice by means of a plaque assay using target cells coated with bovine IgG. CBA mice were high responders and A, and DBA/2 were low responders, while strains C57B1, and LP/J showed low to intermediate responsiveness. Use of appropriate congenic strains confirmed that responsiveness is not closely associated with either H‐2 or Igh. Failure to respond is not likely to be due to a V‐region deficiency, nor can it be readily circumvented, by heterosis (complementation) or the use of high doses of LPS or an extra virulent form of LPS. Breeding experiments show a quantitative trait with maternal responder status having a measurably positive eff