Men with rising prostate-specific antigen (PSA) levels after primary therapies such as prostatectomy or radiotherapy represent a unique group for whom no standard treatment option exists. A variety of approaches including expectant monitoring, dietary modification, hormonal therapy, and alternative medicines have shown an impact on the rate of increase in PSA, but the overall effect on survival remains controversial. At Memorial Sloan-Kettering Cancer Center, we have focused our treatment approach on this cohort of patients in a series of phase I monovalent carbohydrate and glycoprotein-conjugate vaccine trials using the patients' immune system to generate an antitumor response. These synthetic vaccines are conjugated to keyhole limpet hemocyanin (KLH) and given with the immunologic adjuvant QS21 as five subcutaneous vaccines over 26 weeks. All patients generated specific high-titer immunoglobulin M (IgM) and/or IgG antibodies, some of which were able to mediate complement lysis. Preliminary data suggest that these vaccines may impact on the rate of increase in posttreatment PSA slopes compared with pre-PSA values. The impact of vaccine therapy on the PSA slope and its effect on the time to radiographic progression are the current focus of a forthcoming phase II trial. Vaccines may offer an alternative treatment option for the patient who has relapsed early following primary therapies.