Early cutaneous Lyme disease, erythema migrans, manifests as a gyrate erythema at the site of a tick bite. The standard histopathologic description is that of a superficial and deep perivascular lymphocytic infiltrate in which plasma cells are identified at the periphery of the lesion and eosinophils in the center. Deviation from these commonly accepted histopathologic findings may lead to an erroneous diagnosis. Herein, we describe 4 cases of erythema migrans, all biopsied at the periphery of the lesion and confirmed by serologic studies, demonstrating a variety of unconventional histopathologic patterns. These findings include eosinophils and neutrophils at the periphery of the expanding annular plaque of erythema migrans, focal interface change, spongiosis, involvement of the superficial vascular plexus alone, and an absence of plasma cells in all cases. These cases highlight the varied and nonspecific histopathologic changes that can be seen in erythema migrans, including the absence of plasma cells and the presence of focal interface change. Based on these findings, the dermatopathologist should always consider erythema migrans as a diagnostic possibility in a biopsy specimen from an expanding gyrate or annular erythema despite the presence of unusual features. In atypical clinical cases, serologic confirmation may be required for diagnosis in the presence of histopathologic findings considered unconventional for erythema migrans.