Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA AstraZeneca, DE) is a widely used topical anesthetic cream for preprocedural cutaneous analgesia. In addition to potential clinical cutaneous and systemic adverse effects, EMLA may also induce microscopic changes detectable by light and electron microscopy leading to difficulty in accurate diagnosis. We report the case of a biopsy demonstrating EMLA-induced histopathologic changes. The biopsy was taken from the back of a 5-month-old infant and submitted to rule out psoriasis. Hematoxylin and eosin (H&E) staining of the biopsy demonstrated spongiosis and a noninflammatory subepidermal bulla, raising the histopathologic possibility of epidermolysis bullosa. Further investigation confirmed that EMLA was applied under occlusion before biopsy. A second biopsy without topical anesthetic did not demonstrate a bulla and supported the clinical diagnosis of psoriasiform dermatitis. Our case highlights the importance of awareness of EMLA-induced histopathologic changes to avoid potential misdiagnosis. The histopathologic findings of this case in conjunction with other previously reported cases of EMLA-induced bullae were analyzed. Vacuolization of the basal and suprabasilar layer, pallor and swelling of upper layer epidermal keratinocytes, a pauci-inflammatory cleavage beneath or within the basal layer, basophilic granular karyorrhectic debris in the subepidermal cleft, and congestion of papillary dermal vessels characterized the biopsy findings of this localized adverse reaction.