The distinction between primary cutaneous B-cell lymphoma and B-cell pseudolymphoma on a histologic basis may be difficult, particularly in some cases of Borrelia burgdorferi-associated lymphoid proliferations. We report two cases of B burgdorferi-associated pseudolymphoma that showed a dense infiltrate with a predominance of large atypical B cells. Because of this misleading histologic feature, a diagnosis of primary cutaneous large B-cell lymphoma was first suspected in both cases. In one case, successive recurrences led to aggressive therapies before the B burgdorferi infection was recognized. However, a detailed review of histologic and immunohistochemical features was finally suggestive of a B burgdorferi-associated pseudolymphoma in both cases. The etiologic role of B burgdorferi was confirmed by serology, polymerase chain reaction analysis of B burgdorferi DNA within the lesional skin, and response to antibiotic therapy. Because the distinction between B burgdorferi-associated pseudolymphoma and primary cutaneous B-cell lymphomas may be difficult and true B burgdorferi-associated B-cell lymphomas have been described, we suggest that antibiotic therapy should be considered as a first-line treatment in suspected or confirmed cases of primary cutaneous B-cell lymphoma in regions with endemic B burgdorferi infection. (J Am Acad Dermatol 2002;47:530-4.)