Eugenol depressed cell respiration in homogenates of human dental pulp and in mouse fibroblast monolayers. The depression was concentration-dependent, with a threshold at about 10(-4)M and a maximum at 10(-3)M in both preparations. Onset of the depression appeared to be rapid. The effects of variation in both duration and concentration of eugenol exposure on subsequent uptake of 3H-thymidine were examined in mouse fibroblast monolayers and human pulp explants. Fibroblasts survived short-term (up to 12 hr) exposure to 10(-3)M eugenol or less, but died after exposure to 10(-3)M for one day or more. The cells survived exposure to 10(-4)M for ten days, the longest period examined. Human pulp maintained in tissue culture medium showed similar eugenol susceptibility. Analysis of these data, when coupled with those of previous studies on eugenol release from ZOE and diffusion through dentin, gives strong support for the concepts that: the blandness of ZOE when applied to intact dentin is due to eugenol reaching the pulp in sub-toxic concentrations, and the irritant effect of ZOE when applied directly to soft tissue is due to the development of concentrations of eugenol in tissue adjacent to ZOE sufficient to inhibit respiration and thus kill cells.