HIV infection is associated with B cell dysfunction, which includes B cell hyperactivation, hypergammaglobulinemia, impaired production of antibodies against specific antigens, and a loss of B cell memory. Because lymph node architecture is progressively destroyed during HIV infection, it is possible that normal B cell trafficking is impaired as well, which could be a cause or a result of these abnormalities. Because the homeostatic chemokine, CXCL13 (BLC, BCA-1), is a major regulator of B cell trafficking, we assessed circulating levels of this molecule in HIV infection. Serum levels of CXCL13 were seen to be progressively elevated in HIV disease. Serum levels of CXCL13 correlated strongly with those of the inflammation-associated chemokine, inducible protein-10 (IP-10), in subjects who had advanced HIV disease, and more moderately with levels of soluble CD30 (sCD30), sCD27, and sCD23. CXCL13 levels also correlated moderately with viral load and showed a significant decline after use of highly active antiretroviral treatment (HAART). Elevated levels of CXCL13 could cause impaired or altered trafficking of B cells during HIV infection and could contribute to the previously reported loss of CXCR5, the receptor for CXCL13, from the surface of circulating B cells in HIV infection.