Key Points• Heparin rechallenge despite prior HIT often induces platelet-activating anti-PF4/ heparin antibodies but no faster than seen with typical HIT.• Risk of HIT recurring after heparin rechallenge is low but possible if IgG with heparinindependent plateletactivating properties are made.Heparin reexposure despite a history of previous heparin-induced thrombocytopenia (HIT) can be appropriate if platelet-activating antibodies are no longer detectable. We determined the frequency, timing, and magnitude of the antiplatelet factor 4 (anti-PF4)/ heparin immune response (by serotonin-release assay [SRA] and enzyme-immunoassay [EIA]), and the frequency of recurrent HIT in 20 patients with previous HIT reexposed to heparin 4.4 years (mean) post-HIT; 17 patients were given heparin intraoperatively (without postoperative heparin) for cardiac/vascular surgery. One patient developed recurrent HIT beginning 7 days after cardiac surgery, with newly regenerated HIT antibodies exhibiting strong heparin-independent platelet-activating properties. Intraoperative heparin induced EIA seroconversion in 11/17 (65%) patients (immunoglobulin G [IgG]>IgA>IgM) and SRA seroconversion in 8/17 (47%), whereas none of 3 medical patients reexposed to heparin developed seroconversion. Anti-PF4/heparin IgG became detectable at day 7 (median), ie, no sooner than observed in typical-onset HIT. The high proportion of SRA positivity among EIA-seroconverting patients (8/11 [73%]) suggests that patients with previous HIT may be especially predisposed to forming recurrent antibodies with platelet-activating properties. We conclude that among patients with a previous history of HIT who are reexposed to intraoperative (but not postoperative) heparin, the risk of recurrent HIT appears to be low, but is possible if antibodies with strong heparin-independent platelet-activating properties are formed. (Blood. 2014;123(16):2485-2493