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.