Although pathological muscle pain involves a significantly larger population than any other pain condition, the central mechanisms are less explored than those of cutaneous pain. The aims of the study were to establish the pain matrix for muscle pain in the full head volume and, further, to explore the possibility of a functional segregation to nonpainful and painful stimuli within the area of the parasylvian cortex corresponding to the secondary somatosensory area. Additionally, we speculate that a randomization of nonpainful and painful stimuli may target specific structures related to stimulus salience. We used event-related functional magnetic resonance imaging (MRI) and the high sensitivity of the 3-T MRI scanner to study the central processing of acute muscle pain induced by intramuscular electrostimulation. Brief nonpainful and painful stimuli (1-ms duration, interstimulus interval = 12 s) were randomly applied to the left abductor pollicis brevis of 10 subjects. The data disclose a pain matrix for muscle pain similar to that for cutaneous pain. Individual analysis suggests separate representations within the area bounded by the upper bank of the Sylvian fissure (SF) and the circular sulcus of insula (CSI). Nonpainful stimulation activated the superficial parietal operculum adjoining the SF, while the painful condition additionally targeted the deeper parietal operculum bordering the CSI. Randomization of stimuli of different intensities likely introduces cognitive components that engage neural substrates servicing the appreciation of stimulus salience in the context of affect-laden pain imposition.