We studied the plasma of 18 patients with a functional deficiency of plasma prekallikrein (Fletcher trait). Samples from 13 subjects contained less than 1 per cent of normal levels of prekallikrein antigen recognized by a specific antiserum (cross-reacting-material negative [CRM-]). In the five other subjects, however, nonfunctional material immunologically indistinguishable from normal prekallikrein was detected by radioimmunoassays at concentrations of 13 to 30 per cent (CRM+ variant). None of the plasma samples contained detectable circulating anticoagulants against prekallikrein. On immunodiffusion against antiserum to kallikrein, each of the five CRM+ samples formed a single precipitin line of complete identity with normal plasma or purified prekallikrein. On immunoelectrophoresis, the precipitin line had the same mobility as that for normal prekallikrein. These studies demonstrate the molecular heterogeneity of human prekallikrein deficiency and show that persons with the CRM+ variant have a nonfunctional form of prekallikrein in their plasma.