Liposomal daunorubicin replacing conventional anthracyclines may reduce toxicity and enhance efficacy of chemotherapy. In this phase I study, we evaluated liposomal daunorubicin (DaunoXome) in combination with vincristine and dexamethasone for toxicity, pharmacokinetics and potential efficacy in patients with multiple myeloma. The main objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of liposomal daunorubicin combined with vincristine and dexamethasone (VLDD). Additionally, pharmacokinetics were determined at higher dose levels. Seventeen multiple myeloma patients were enrolled in this trial; 76% of the patients had relapsed or refractory multiple myeloma. Successive cohorts received liposomal daunorubicin at doses of 40, 60, 80 and 100 mg/m2on day 1 in combination with vincristine 1.4 mg/m2(day 1) and oral dexamethasone (40 mg, days 1–4). DLT occurred at 100 mg/m2. Liposomal daunorubicin at 80 mg/m2was well tolerated in this protocol and should be used for further phase II studies with the VLDD regimen. In this phase I trial, 64% of the patients achieved a partial remission or a minor response.