This study was conducted to evaluate the pulpal response to direct capping with either mineral trioxide aggregate (MTA) or calcium hydroxide (CH) cement in humans, with a focus on dentin bridge formation and dentin sialoprotein (DSP) and heme oxygenase-1 (HO-1) expression. Direct pulp capping was performed in 20 cases of caries-free human third molars. The pulps were exposed and capped with either MTA or hard-setting CH. After 2 months, the teeth were extracted, and the specimens were prepared for histologic and immunohistochemical evaluations. Histologically, 100% of the MTA group and 60% of the CH group developed dentin bridges. The mean thickness of the dentin bridges observed in the MTA group was statistically greater than that of CH group. In addition, DSP and HO-1 were expressed in the odontoblast-like cells and pulp fibroblasts beneath the dentin bridge; furthermore, significantly greater immunostaining was observed in the MTA group than in the CH group. Collectively, these results indicate that MTA is superior to CH in terms of inducing the dentinogenic process in human pulp capping.