We present three patients with syphilis in which the prozone phenomenon was present--a very high antibody titer, leading to a false-negative test in undiluted specimens. One of our three patients was positive for human immunodeficiency virus (HIV), another was at risk for HIV infection, and had some clinical findings compatible with HIV infection (this patient was seen before HIV serologic tests were available). We propose that HIV infection, by its B-cell dysregulation, may lead to higher nontreponemal serologic titers, raising the possibility that the prozone phenomenon may be more prevalent in HIV-positive individuals with syphilis than in luetic patients who are negative for HIV.