Chemotherapeutic agents (CT) and ionizing radiation (X-ray) induce DNA damage and primarily aim to stop the proliferation of tumor cells. However, multimodal anti-cancer therapies should finally result in tumor cell death and, best, in the induction of systemic anti-tumor immunity. Since distinct therapy-induced tumor cell death forms may create an immune activating tumor microenvironment, this study examined whether sole treatment with CT that are used in the therapy for colorectal cancer or in combination with X-ray result in colorectal tumor cell death with immunogenic potential. 5-Fluorouracil (5-FU), Oxaliplatin (Oxp), or Irinotecan (Irino) in combination with X-ray were all potent inhibitors of colorectal tumor cell colony formation. This study then examined the forms of cell death with AnnexinA5-FITC/Propidium Iodide staining. Necrosis was the prominent form of cell death induced by CT and/or X-ray. While only a combination of Irino with X-ray leads to death induction already 1 day after treatment, also the combinations of Oxp or 5-FU with X-ray and X-ray alone resulted in high necrosis rates at later time points after treatment. Inhibition of apoptosis increased the amount of necrotic tumor cells, suggesting that a programmed form of necrosis can be induced by CT + X-ray. 5-FU and Oxp alone or in combination with X-ray and Irino plus X-ray were most effective in increasing the expression of RIP, IRF-5, and p53, proteins involved in necrotic and apoptotic cell death pathways. All treatments further resulted in the release of the immune activating danger signals high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). The supernatants of the treated tumor cells induced maturation of dendritic cells. It is, therefore, concluded that combination of CT with X-ray is capable of inducing in vitro cell death forms of colorectal tumors with immunogenic potential.