Infection with HIV-1 is known to impair B cell function. To further elucidate the role of B cells during infection and tumorigenesis, we studied their numbers in cases of AIDS-related Kaposi's sarcoma (KS) during the HAART era. Patients with AIDS-related KS were identified from a database of 4,480 HIV-1 positive individuals and the incidence of KS and rate ratio was stratified according to nadir number of B cells, measured as the CD19 count. In an unadjusted model, we observed that lower B cell counts were associated with a statistically significant increased risk of KS development (p < 0.001). We also observed a trend toward increased counts during KS resolution. When adjusted for nadir CD4 count in a multi-variable model, higher B cell counts were protective against KS development (p = 0.015). These data highlight a potential role for B cells and therefore the humoral immune system in KS aetiopathogenesis. © 2003 Wiley-Liss, Inc.