Induction of apoptosis in tumor cells by TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a promising therapeutic principle in oncology, although toxicity and resistance against TRAIL are limiting factors. Taurolidine (TRD), an antineoplastic agent with low toxicity, is a potential candidate for combined therapy with TRAIL. The aim of this study was to evaluate the apoptotic effects of a combined treatment with TRD and TRAIL in a human HCT-15 colon carcinoma cell line. HCT-15 cells were incubated with increasing concentrations of recombinant human TRAIL (50 ng/mL to 500 ng/mL) or TRD (50 micromol/L to 1000 micromol/L). In a second experiment, cells were furthermore exposed to a combination of both substances (TRAIL 50 ng/mL and TRD 100 micromol/L). At various time points (3 h to 36 h), cell viability, apoptosis, and necrosis were quantified by FACS analysis (propidium iodide/annexin V-FITC) and confirmed by TUNEL assay. Incubation with TRD resulted in cell death induction with maximum effects observed at 100 micromol/L and 1000 micromol/L after 36 h. TRAIL application led to dose-dependent cell death induction as early as 6 h. Combined treatment of TRD (100 micromol/L) and TRAIL (50 ng/mL) caused a sustained induction of apoptosis that was superior to single-agent application, exceeding a merely additive effect. Combinatory treatment of human colon carcinoma cells with TRD and TRAIL results in a synergistic effect on apoptosis induction with a significant increase of the apoptotic index. Combination of TRAIL with the nontoxic TRD might represent a novel therapeutic strategy in oncological therapy.