Atopic dermatitis (AD) is prone to exacerbations in response to various triggering factors and flare-ups after remission. We searched for molecules associated with relapse/exacerbation of AD among molecules with altered gene expression in the skin of patients with AD. Microarray analyses were performed on lesional and nonlesional skin of adolescent or adult patients with recalcitrant AD and healthy controls. Five chaperones involved in intracellular stress responses, namely heat shock protein family A (Hsp70) member 9 (HSPA9), heat shock protein 90 beta family member 1 (HSP90B1), calnexin (CANX), malectin (MLEC
endoplasmic reticulum-associated degradation), and heat shock protein family D (Hsp60) member 1 (HSPD1), were consistently upregulated in involved and uninvolved skin of patients with AD. Damage-associated molecular patterns were upregulated in involved skin. KLF transcription factor 2 (KLF2) was decreased in involved skin and exhibited a decreasing trend in uninvolved skin of patients with AD. CD4(+)/CD8(+) double-positive cells (1.4% of T cells) were detected in lesions with declined KLF2 levels. WNT inhibitory factor 1 (WIF1) was downregulated in involved skin. Prolactin-induced protein was upregulated in only uninvolved skin of patients with AD. We found increased intracellular stress responses and decreased expression of KLF2 in the skin of patients with AD. Multifactorial genetic diseases, such as asthma, inflammatory bowel disease, type 2 diabetes, and rheumatoid arthritis, are associated with intracellular stress. Intracellular abnormalities may also be responsible for AD. Further research on AD may incorporate enhanced intracellular stress response and the decreased expression of KLF2 into the mechanism underlying AD.