We have demonstrated previously that pemphigus vulgaris (PV)-IgG induces activation of phospholipase C (PLC), production of inositol 1,4,5-trisphosphate, and a rapid transient increase in [Ca²⁺] in cultured human keratinocytes, leading to secretion of plasminogen activator and cell–cell detachment in cell culture. In the current study, to examine the involvement of protein kinase C (PKC) in the mechanism of blister formation in PV, we studied the PV-IgG-induced translocation of PKC isozymes from the cytosol to the particulate/cytoskeleton (p/c) fractions and the activation of PKC in human keratinocytes. Cells cultured in Eagle’s minimum essential medium were incubated with PV-IgGs for 30 s, 1 min, 5 min, or 30 min. PV-IgG binding to the cell surface antigen (desmoglein III) induced translocation of PKC-α from the cytosol to the p/c fractions within 30 s, with a peak at 1 mm that lasted at least 30 mm. PKC-δ also was translocated within 1 min and reached a peak at 5 min but was reduced to basil levels at 30 min. Alternatively, PKC-η translocation to the p/c fraction was induced slowly, taking more than 5 min, and was reduced to approximately half-maximum at 30 min, whereas PKC-ζ translocation reached a maximum at 30 s, rapidly returning to baseline by 5 min after PV-IgG stimulation. The total PKC activity in the p/c fraction also was increased after PV-IgG exposure, peaked at 1 min, and was sustained for at least 30 min. These findings suggest that a unique activation profile of PKC isomers may be involved in mediating the intracellular signaling events induced by PV-IgG binding to desmoglein III in cultured human keratinocytes.