Pain in older adults with severe limitations in ability to communicate is often assessed with observational methods. However, many of the behaviors that are used to assess pain often overlap with behavioral manifestations of delirium and depression. Such overlap can make the assessment of pain in patients with comorbid delirium and/or depression especially challenging. In this study, we assessed pain using the Doloplus-II (one of the most established pain assessment methods for seniors with dementia) and examined the extent to which each of its items were also predictive of delirium, depression, and dementia severity. As expected, several Doloplus-II items were found to be related to dementia severity, depression, and/or delirium. Clinicians assessing pain in dementia patients with comorbid depression or delirium should place less emphasis on items that have reduced specificity in identifying pain problems. Instead, assessment should be informed by items with higher specificity as well as other sources of information (e.g., results of physical examinations and information from caregivers). Although in this investigation we used the Doloplus-II to assess pain, it is likely that our findings generalize to other observational pain assessment measures developed for patients with dementia.