Human papillomaviruses (HPV) are small DNA tumor viruses, and are associated with epithelial neoplasias. Although HPV are believed to be exclusively permissive in terminally differentiated squamous cells, we have previously identified HPV sequences in lymphoid tissues of five patients. Because this result suggested that the range of the host virus cells could include cells of lymphoid origin, we used PCR and in situ hybridization to analyze nonepithelial tissues of patients with multiple myeloma from two institutions. A statistically significant association was established between HPV and multiple myeloma (p<0.001). This study supports the hypothesis that HPV can infect lymphoid cells.