Objectives: To study psychological distress in a sample of caregivers of patients affected by prolonged disorders of consciousness during hospital stay in the Neurorehabilitation Unit. Materials and methods: Twenty-four caregivers of 22 patients affected by prolonged disorders of consciousness admitted to postacute rehabilitation center, completed self-reported questionnaires for assessment of depressive symptoms, state and trait anxiety, psychophysiological disturbances, prolonged grief disorder, psychological coping strategies, quality of perceived needs, perceived social support, and caregiver burden; at admission, and after four and eight months. Results: At admission depressive symptoms were found in 20/24 caregivers, high levels of anxiety in 16, and relevant psychophysiological disturbances in 10 participants; eight caregivers (32%) met criteria for prolonged grief disorder. The scores on questionnaires did not differ as a function of relatives’ diagnosis (vegetative state vs. minimally conscious state). The longitudinal study (n = 18) showed a progressive and statistically significant increase of “emotional burden” during the hospital stay, whereas the remaining variables did not change significantly. Conclusions: Data confirmed the presence of severe psychological problems in caregivers of patients with prolonged disorders of consciousness. The levels of psychological distress tend to be constant over time, while the emotional burden increases.