The sign is present when slight rubbing of the skin results in exfoliation of the outermost layer.

Nikolsky's sign is almost always present in Stevens–Johnson syndrome/toxic epidermal necrolysis[5] and staphylococcal scalded skin syndrome, caused by the exfoliative toxin of Staphylococcus aureus.

The Nikolsky sign is dislodgement of intact superficial epidermis by a shearing force, indicating a plane of cleavage in the skin epidermal-epidermal junctions (e.g., desmosomes).

The formation of new blisters upon slight pressure (direct Nikolsky) and shearing of the skin due to rubbing (indirect Nikolsky) is a sign of pemphigus vulgaris, albeit not a 100% reliable diagnosis.

[8] In addition, another physical exam, the Asboe-Hansen signs, must be used to determine the absence of intracellular connections holding epidermal cells together.