The study of thermo-hygrometric comfort in hospitals involves several factors: the presence of different subjects: patients, operators, visitors; different conditions of hospitalization: patients bedridden or out of bed; psychological aspects and therapeutic treatments. In this paper, the analysis focuses on patients in ordinary hospitalization rooms of a hospital located in southern Italy. Different room orientations, several characteristics, and specific factors concerning hospitalized patients’ conditions that significantly influence the comfort indices have been considered. In total, 41 scenarios have been defined and analyzed by means of two comfort models: static and adaptive. The study aims to investigate the application of these models to the complex environment of hospitals, finding strengths and weaknesses, which also results in a re-definition of the HVAC system operation. Results show that patient position (in bed or out), clothing type, and level of coverage in the bed can make the same microclimatic condition more suitable for one scenario over another. Furthermore, room exposure has an effect on the comfort of the indoor temperature. The seasonal analyses highlight that during summer, for all scenarios considering bedridden patients, more than 50% of the PMV calculated values are out of the comfort zone. In winter, the indoor conditions are good for bedridden patients with a cover level of 67% during the nighttime (almost 100% PMV values in comfort zone), while during the daytime, they are more suitable for a 48% coverage level if the patient is in bed or if they are walking (lower than 10% dissatisfied).