This study investigated post-surgical pain in children with profound cognitive impairment (PCI), searching for a core set of cues these children use to express their pain. Fifty-two children were observed while they were admitted to the Sophia Children's Hospital for surgery, twice before and five times after surgery. All observations were scored with the item pool consisting of 134 possible pain indicators, using a five-point scale ranging from 0 (never shown) to 4 (always shown). Second, we used the visual analogue scale (VAS) to give a general impression of the severity of the children's pain during the episodes they were observed. Several analyses provided evidence that 23 observable behaviors are sensitive to post-surgical pain in children with PCI, regardless of the pain intensity of the surgical procedures they underwent. The finding that all indicators, except for one, were scored significantly higher on episodes with VAS ratings >or=4, indicates the sensitivity of these indicators concerning absence versus presence of clinically meaningful levels of pain. This study reveals the potential clinical utility of a core set of indicators which can be used to assess post-surgical pain in children with PCI.