Vaccination with idiotype (Id) protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id- and keyhole limpet haemocyanin (KLH)-pulsed, CD40 ligand-matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id-specific γ-interferon T-cell response. Interleukin-4 response was elicited in two, and skin delayed-type hypersensitivity reaction occurred in seven patients. More importantly, Id-specific cytotoxic T-cell responses were also detected in five patients. Most if not all patients mounted a positive T-cell response to KLH following vaccination. At 1-year follow-up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5-year follow-up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id-pulsed CD40 ligand-matured DCs was able to induce Id-specific T and B-cell responses in patients. Current efforts are geared towards breaking tumour-mediated immune suppression and improving clinical efficacy of this immunotherapy.