Sleep deprivation (SD) is a technique of sleep–wake manipulation which has been used to treat depression. Changes in neurotransmitter systems, that are also involved in the effects of the antidepressant drugs, have been suggested as the possible mechanisms of action of SD. However, the therapeutic effect of SD is acute and transient, while antidepressant effects of drug treatments are gradual and stable. SD might work throughout mechanisms that are different from those mediating drug's effects. In the present study we analyzed the role of dopamine activity in SD. Spontaneous eye blink rate provides a non invasive measure of central dopamine activity. We assessed eye blink rate across prolonged wakefulness (from 10:00 a.m. to 07:00 a.m.) in 25 young normal subjects. Eye blink rate increased at the end of the wakefulness period. Blink rates and sleepiness as assessed by Karolinska Sleepiness Scale correlated positively with time spent awake. We propose that increased blink rate might reflect a dopamine activation that counteracts sleep drive. Antidepressant effects of sleep deprivation might be related to activation of the physiological mechanisms which regulate wake maintenance.