Background: Radiation toxicity in monotherapy has been widely studied, together with its possible combinations with chemotherapy and targeted therapy. Now that immunotherapy is increasingly being used in cancer treatment, the combination of radiation and immunotherapy and its specific toxicity needs to be understood and properly addressed. The aim of this chapter is to focus on that toxicity that is usually unknown and underdiagnosed in this combination therapy and that has potential morbidity and mortality for patients. Methods: The analyses of the scientific literature on immunotherapy toxicity showed that there are at least three organs affected in this combination therapy that are difficult to detect and mostly underdiagnosed: endocrine toxicity, cardiotoxicity, and ocular toxicity. Experts in the field gave data on the difficult diagnosis, tests to be taken into account, possible treatments, and future considerations. Results: Mechanisms of action through which radiotherapy and immunomodulatory drugs interact could explain an overlap in terms of toxicity. However, data extracted from numerous retrospective and prospective studies by the experts provide initial evidence that the combination of radiotherapy and immunotherapy is safe. Nevertheless, underdiagnosed, and underreported toxicity such as endocrine, cardiac, and ocular toxicity urge to be specifically addressed in future prospective clinical trials, as there is sufficient undirected data stating their existence and sometimes chronic nature. Conclusions: The combination of radiotherapy and immunotherapy has not demonstrated a higher toxicity to date compared to immunotherapy alone. However, experts in the field advice for a careful evaluation of the radiation scheme to be administered in these combinations, in order to avoid major toxicities as well as advising for a multidisciplinary approach for detecting underdiagnosed endocrine, cardiac, and ocular toxicity.