PWS Smart-Start is a behavioral caregiver training program developed specifically for caregivers of children with Prader-Willi syndrome (PWS) ages 3 to 14. The purpose of the current study was to evaluate the acceptability and preliminary efficacy of the program. Thirty-four caregivers of children with PWS received the PWS Smart-Start training using online live video-coaching across a 10-week period. The impact of the training on a variety of variables including caregiver and child behavior, caregiver stress and burnout, and family functioning were evaluated using a quasi-experimental pretest posttest design. Results indicated statistically significant decreases across child behavior challenges and parental stress and burnout following the training. Statistically significant improvements were also seen in parenting practices, the quality of the parent-child relationship, and family quality of life. Results of social validity measures indicated caregiver satisfaction with the program. These preliminary results indicate that the PWS Smart-Start program has the potential to not only support children with PWS through behavioral challenges but also reduce caregiver stress and burnout and improve a variety of aspects of family life. Future research is needed to replicate and further validate these results and to extend the exploration of other behavior analytic interventions for this population.