The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0·002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial.