Calcium is an essential co-factor in antigen-evoked histamine release reaction in vitro from human skin passively sensitized with reaginic antibody (IgE antibody). The reaction could be divided into two stages, an initial calcium-independent stage of antigen antibody combination (first stage) and a late calcium-dependent stage of histamine release reaction (second stage). The reaction of antigen-antibody combination in first stage took place rapidly. The magnitude of histamine release in the second stage (calcium-dependent stage) was almost equal to that of histamine release produced by incubation of sensitized skin slices with antigen in the presence of calcium at normal concentration. The first stage was stable at least for 15 min because prolongation of the first stage up to 15 min at 37 °C was not followed by any reduction of histamine release on subsequent recalcification.