Combining thalidomide (Thal) with chemotherapeutic agents or steroid preparations led to improved response rates in the treatment of multiple myeloma. However, deep vein thrombosis (DVT) is one of the most serious side-effects noted with this regimen, and how a Thal-based regimen causes DVT is unclear. We investigated the procoagulant effects of Thal when combined with chemotherapeutic agents in vitro, focusing on tissue factor (TF) and phosphatidylserine. We examined the effects of the chemotherapeutic doxorubicin hydrochloride (Dox) and the steroid dexamethasone (Dex), with or without Thal. Our study used the human vascular endothelial, monocytic, and myeloma cell lines, EAhy926, THP-1, and RPMI8226, respectively. In EAhy926 and THP-1, Dex treatment increased expression of TF, which may induce procoagulant activity (PCA). Upregulation of TF mRNA correlated with activation of the Egr-1 pathway. In Thal and Dex treatments, the increase of PCA induction from phosphatidylserine exposure was modest. In contrast, Dox and Thal-Dox increased phosphatidylserine exposure in both cell types. In THP-1 cells, cell surface phosphatidylserine exposure correlated with increased PCA by Dox. Thal alone showed a modest increase in phosphatidylserine exposure in endothelial cells and monocytes. When Thal is given in combination with chemotherapies or Dex, endothelial cell and monocyte PCA may be induced through phosphatidylserine exposure, or TF expression. Induction may be protracted by Thal, which has an antiangiogenic activity. Therefore, prophylactic anticoagulant strategies should be considered in Thal-based combination regimens.