Purpose: Offshore Ocean Sailing is a highly demanding activity in which subjects are exposed to psychophysical stressors for a long time. To better define the physiological adaptations, we investigated the stress response of subjects exposed to 3-days long ocean navigation with disruption of circadian rhythms.Methods: 6 male subjects were involved in the study and provided urine and saliva samples before setting sail, during a single day of inshore sailing, during 3-days long ocean navigation, and at the arrival, to measure oxidative stress, cortisol, nitric oxide metabolites (NOx) and metabolic response. Motion Sickness questionnaires were also administered.Results: The crew suffered a mean weight loss of 1.58 Kg. After the long navigation, a significant increase in ROS production and decreased antioxidant capacity and uric acid levels were observed. Lipid peroxidation, NOx, ketones, creatinine, and neopterin levels were also increased. A significant increase in cortisol levels was recorded, but no correlation was found with motion sickness questionnaires that were instead correlated with the rise of NOx.Conclusions: physical and psychological stress response derived from offshore sailing resulted in increased oxidative stress, nitric oxide metabolites, and cortisol levels, unbalanced redox status, transient renal function impairment, and ketosis. A direct correlation between motion sickness symptoms evaluated through questionnaires and NOx levels was also found.