In a controlled multiple case design study, the development of a therapeutic relationship and its role in affect regulation were studied in 6 children with visual disabilities, severe intellectual disabilities, severe challenging behavior, and prolonged social deprivation. In the 1st phase, children had sessions with an experimental therapist stimulating therapeutic attachment, alternating with a control therapist providing positive personal attention only. In the 2nd phase, both therapists applied behavior therapy. Clients sought more proximity to the experimental therapist compared with the control therapist. Psychophysiological arousal (respiratory sinus arrhythmia and pre-ejection period) was lower when the experimental therapist applied behavior modification than when the control therapist did. Despite prolonged social deprivation, the attachment behavioral system appeared responsive to stimulation. The effects on affect regulation may explain the synergy between psychotherapy based on interpersonal and behavior modification approaches. © 2009 American Psychological Association.