This study investigated the immunomodulatory effects of low-dose interferon-alpha (IFN-alpha) in a cohort of 21 stage II or III melanoma patients treated in an adjuvant setting. Serial assessments in peripheral blood were performed at baseline and at regular intervals. Depletion of CD3+CD4+ T cells was predominant within the "central memory" and "memory" subsets. The impact of IFN-alpha was more marked at the level of all CD3+CD8+ T-cell subsets that showed a sustained and significant decrease. Both myeloid and plasmacytoid dendritic cell (DC) subsets were depleted, but the MDC/PDC ratio tended to increase 12 months after treatment. Also, CD14+CD16+ monocytes showed a significant increase of both MHC class I and the CD86 costimulatory molecule. IP-10/CXCL10 plasma levels significantly increased already at 3 months of therapy and remained at significantly high levels during the study period. The dramatic increase of IP-10/CXCL10 inversely correlated with a significant decrease of the CXCR3+CD8+ T lymphocytes. Low-dose IFN-alpha therapy can significantly affect phenotypic and functional properties of blood circulating lymphocytes and antigen-presenting cells, and production of IP-10/CXCL10, that appear to be important for the orchestration of an effective immune response during adjuvant IFN-alpha therapy for melanoma.