The decision as to whether a sensation is perceived as painful does not only depend on sensory input but also on the significance of the stimulus. Here, we show that the degree to which an impending stimulus is interpreted as threatening biases perceptual decisions about pain and that this bias toward pain manifests before stimulus encounter. Using functional magnetic resonance imaging we investigated the neural mechanisms underlying the influence of an experimental manipulation of threat on the perception of laser stimuli as painful. In a near-threshold pain detection paradigm, physically identical stimuli were applied under the participants' assumption that the stimulation is entirely safe (low threat) or potentially harmful (high threat). As hypothesized, significantly more stimuli were rated as painful in the high threat condition. This context-dependent classification of a stimulus as painful was predicted by the prestimulus signal level in the anterior insula, suggesting that this structure integrates information about the significance of a stimulus into the decision about pain. The anticipation of pain increased the prestimulus functional connectivity between the anterior insula and the midcingulate cortex (MCC), a region that was significantly more active during stimulation the more a participant was biased to rate the stimulation as painful under high threat. These findings provide evidence that the anterior insula and MCC as a “salience network” integrate information about the significance of an impending stimulation into perceptual decision-making in the context of pain.