Patients who develop lymph node metastases from melanoma are known to be at risk of developing further recurrences from melanoma following surgical removal of lymph node metastases. The purpose of the present study was to examine whether immunization over a 2 year period with a vaccine made from vaccinia viral lysates of an allogeneic melanoma cell (VMCL), following surgical removal of lymph node metastases, would help prevent the development of distant metastases and improve survival from the disease. Eighty patients treated with VMCL alone and followed for a minimum of 5.5 years had improved survival compared to a historical control group of 151 patients and a concurrent non-randomized group of 55 patients. Similarly, the survival of 102 patients treated with VMCL + low dose cyclophosphamide for a minimum of 3.5 years was superior to that of the historical control group but not to that of the VMCL alone treated group. Improvement in survival was still evident when this was measured from the date of removal of the primary tumor. Analysis of subsets of patients showed that VMCL treatment appeared to benefit patients irrespective of the number of lymph nodes involved and whether surgery was carried out near to (synchronous metastases) or some time after removal of the primary (delayed metastases). Analysis of the effect of treatment on duration to development of distant metastases suggested that there was a lower proportion of metastases during treatment with VMCL compared to the historical control groups. Treatment with VMCL also appeared to be associated with a lower incidence of cutaneous metastases but a higher proportion of visceral (including liver) metastases. Treatment was not associated with prolongation of survival after development of distant metastases. The results from this prolonged follow-up provide further support for an apparent survival benefit from immunotherapy with VMCL and suggest that the duration to and site of distant metastases is altered by this treatment. A randomized control (Phase III) study based on these results is in progress.