Pustulosis palmaris et plantaris (PPP) is a chronic relapsing skin disease characterized by sterile intraepidermal pustules and, usually, by scaly erythematous skin on the palm, soles, or both. To determine the primary pathogenic factors involved in the onset of PPP, we analyzed the implications of heat shock proteins (HSPs), which are highly conserved immunogenic proteins, chronic microbial infections including marginal and periapical periodontitis, and delayed type hypersensitivity (DTH) against dental metals examined by patch tests. We found that the titers of IgG against HSPs of Escherichia coli GroEL and Actinobacillus actinomycetemcomitans DnaJ in the sera from PPP patients were higher than those in the control group (GroEL; pϽ0.05). Two patients with PPP had more than 1,000 ng/ml serum IgE level. We found that the average serum IgG antibody level against human cytomegalovirus (HCMV) in the PPP patient group was higher than that of the healthy group (pϽ0.05). DTH against dental metal was found in eight of 22 PPP patients. Six of eight patients reacted against more than two metals. Replacement of dental metal with resin in these patients resulted in the disappearance or remission of PPP. These findings suggest that the immune responses to HSPs produced by oral bacteria, HCMV infection, dental metal allergy, and their combinations are etiological factors for PPP. We concluded that various kinds of examinations, including oral cavity conditions and chronic infections, are essential to determine the major etiologic factors of PPP.