Background. Because previous reports suggest that the linear relationship between celite activated clotting time (ACT) values and heparin sodium is disrupted if values exceed 500 to 600 seconds, this study was designed to evaluate the relationship of kaolin activated clotting time (ACT) values to high in vitro heparin concentrations. In addition, the relationship of kaolin ACT to heparin concentration as determined manually was compared with that obtained with an automated heparin dose response assay. Methods. Blood specimens were obtained prior to and after heparin administration from 41 cardiac surgical patients requiring cardiopulmonary bypass in this institutional human studies committee-approved study. Five ACT instruments were used to evaluate the response of kaolin ACT to manually added heparin at two anticoagulation levels: low range (ACT values of less than 500 seconds) and high range (ACT values of 500 seconds or greater). Specimens were also used to measure kaolin ACT values at three heparin concentrations with an automated heparin dose response assay (HDR) using a Hepcon instrument. Results. A greater response of kaolin ACT to heparin was seen with high-range ACT values than low-range ACT values as illustrated by greater (p = 0.002) mean slope values (low range, 99 ± 30 s · U-1 mL-1; high range, 128 ± 50 s · U-1 mL-1). Good correlations were obtained between heparin concentration and either low- or high-range ACT values as demonstrated by mean correlation coefficients (low range, 0.992; high range, 0.982). The response of low-range kaolin ACT-values to heparin was greater than that obtained with the automated heparin dose response assay as illustrated by greater (p = 0.005) mean slope values (low range, 99 ± 30 s · U-1 mL-1; HDR, 82 ± 21 s · U-1 mL-1). Good correlations were observed for the relationship between heparin and ACT values obtained with the HDR assay (r = 0.998). Conclusions. A variable response of kaolin ACT to heparin among patients was demonstrated in our study, especially when ACT values exceeded 500 seconds. We found that the response of kaolin ACT to higher heparin concentrations was acceptable for clinical monitoring based on good correlations obtained in individual patients. The HDR assay generally overestimates a patient's heparin requirements; most likely, this is due to a lower response of kaolin ACT to heparin concentration that is reflected by this assay. Because an exceptional correlation can be obtained between kaolin ACT values and heparin concentration using the assay, this automated assay can identify heparin-resistant patients who may need further treatment.