Background: Physiological responses have been used in individuals with acquired disability to enable communicative interaction without motor movement. This study explored four autonomic nervous system (ANS) signals--electrodermal activity, skin temperature, cardiac patterns and respiratory patterns--to enable interaction with individuals born with profound intellectual and multiple disabilities (PIMD). Method: A series of case studies were conducted to teach a 15-year-old individual with PIMD to voluntarily control his ANS signals for the purposes of communicative interaction. Training was carried out according to an alternating treatment single-subject research design. Results: Training was unsuccessful; however, ANS signal patterns revealed issues unique to people with PIMD: profound intrasubject variability, discrepancy between physiological responses and caregiver perspectives, and the participant's lack of contingency awareness. Conclusions: These three priority areas unique to people with congenital PIMD must be addressed before ANS signals can be used to enable communicative interaction with this population. (Contains 2 tables and 3 figures.)