Background An increased incidence of deep venous thrombosis (DVT) has been described in multiple myeloma (MM). A recently described mechanism of hypercoagulability in cancer patients including MM patients is acquired activated protein C resistance (APC-R). The purpose of the present study was to examine the association between the combination of thalidomide plus chemotherapy and DVT development in a cohort of patients with newly diagnosed multiple myeloma. We also evaluated the association between acquired activated protein C resistance and DVT. Methods Patients with newly diagnosed and symptomatic MM (untreated or with one cycle of preceding chemotherapy) were evaluated. The present study is a prospective, descriptive, longitudinal and observational one. The coagulations tests were performed including: prothrombin time, activated partial thromboplastic time (aPTT), fibrinogen, anticardiolipin antibodies, lupus anticoagulant, antithrombin, protein C and protein S activities, factor VIII, activated protein C (APC) resistance, factor V Leiden, and quantitative D-dimers. Factor V Leiden mutation was detected by analysis of the polymerase chain reaction amplification of genomic DNA. Results Fifty newly diagnosed multiple myeloma patients were included in the study. DVT was developed in 8 patients (16%). Six patients were confirmed to have acquired activated C protein resistance. All of them were tested twice. Four out of 6 patients developed DVT (66%), all of them received thalidomide at a median dose of 200 mg qd. Conclusion APC-R appears to be a transitional condition that may be related to myeloma status. Thrombotic complications can affect morbidity and even mortality in these patients. To fully evaluate the potential synergistic anticancer activity of combinations of chemotherapy and thalidomide, effective prophylactic anticoagulation should be implemented in all controlled trials, at least during the first few cycles of treatment.