Objectives: The aim of the experiment was to analyze the influence that the clothing material may have on human physiology and thermal comfort both at rest and physical effort to answer the question which fabric is better, a natural or a synthetic one. Materials and Methods: We measured some psychomotor parameters: critical flicker frequency (CFF), reaction time to auditory/visual stimuli (RT), concentration of attention (CA); cardiovascular parameters: blood pressure (BP), heart rate (HR) and respiratory parameters: tidal volume (V T ), minute ventilation (V E ), oxygen consumption (V O2 ), carbon dioxide output (V CO2 ), respiratory exchange ratio (RER) in human volunteers before, during and after physical effort. The subjects performed a 15-min treadmill test on treadmill wearing clothes made of two different materials: 100% coarse wool and 100% acrylic. An interview was conducted directly before the exercise test to assess the subjects' general mood and wellbeing on that day. Besides, before and after the test, the subjects in their own words described the sensation they felt with respect to the physiological comfort of particular clothing. Results: The results showed that wearing clothes made of different fabrics had some influence on the cardiovascular and respiratory parameters during physical effort but it did not have any effect on the psychomotor skills. The perception of physiological comfort by the subjects wearing coarse wool or acrylic depended on their physiological state and differed at rest and after the physical effort. Conclusions: The course of physiological processes depends on the kind of clothing a given person is wearing. It is not possible to clearly define which of the two clothing materials: natural -wool, or synthetic -acrylic is better. Each of them exerts a different effect on the human organism. The usefulness of a given type of clothing material seems to depend on the human physiological state and the related thermoregulatory processes.