The aim of this phase 1 clinical trial was to test the safety and feasibility of a single dose of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with severe sepsis. This is a single-center, open-label, dose-escalation phase 1 clinical trial of a single dose of intravenous MSCs in patients with severe sepsis. We enrolled 15 patients who averagely divided into low (1×106 cells/kg), intermediate (2×106 cells/kg), and high (3×106 cells/kg) dosing cohorts. Primary outcomes included the incidence of infusion-associated events and serious adverse events. Secondary outcomes included systemic endpoints, mortality, and inflammation biologic markers. A historical case-matched comparison group was set as the control. This study enrolled 15 patients (10 male and 5 female), with a median age of 58. Compared to those in the historical, case-matched group, neither there were infusion-associated serious events or treatment-related adverse events in any of the 15 patients in this trial, nor were there any safety or efficacy signals for serious adverse events or the measured cytokines. A single intravenous infusion of allogeneic MSCs up to a dose of 3×106 cells/kg was safe and well tolerated in 15 patients with severe sepsis.