Thalidomide with dexamethasone (thal-dex) is an active therapy for patients with relapsed or refractory multiple myeloma (MM). In this Practice Point, we discuss the findings of a trial by Rajkumar et al. that aimed to compare the response rate, time to progression and progression-free survival among previously untreated patients with MM who received either thal-dex or placebo plus dexamethasone. The thal-dex regimen was associated with a significantly higher response rate at the expense of more-frequent adverse effects, in particular deep-vein thrombosis, which occurred in almost 20% of patients. Median time to progression was three times longer with thal-dex than with placebo plus dexamethasone, but was shorter, however, than the time to progression observed in studies in which thalidomide or bortezomib was added to melphalan and prednisone. Nevertheless, thal-dex is a convenient oral and relatively inexpensive non-myelosuppressive regimen, which can be used in patients with previously untreated MM.