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Propofol is one of the most commonly used anesthetics in the world, but much remains unknown about the mechanisms by which it induces loss of consciousness. In this resting-state functional magnetic resonance imaging study, we examined qualitative and quantitative changes of resting-state networks (RSNs), total brain connectivity, and mean oscillation frequencies of the regional blood oxygenation level-dependent (BOLD) signal, associated with propofol-induced mild sedation and loss of responsiveness in healthy subjects. We found that detectability of RSNs diminished significantly with loss of responsiveness, and total brain connectivity decreased strongly in the frontal cortex, which was associated with increased mean oscillation frequencies of the BOLD signal. Our results suggest a pivotal role of the frontal cortex in propofol-induced loss of responsiveness.