Objective To study the effect of pediatric physical therapy on positional preference and deformational plagiocephaly. Design Randomized controlled trial. Setting Bernhoven Hospital, Veghel, the Netherlands. Participants Of 380 infants referred to the examiners at age 7 weeks, 68 (17.9%) met criteria for positional preference, and 65 (17.1%) were enrolled and followed up at ages 6 and 12 months. Intervention Infants with positional preference were randomly assigned to receive either physical therapy (n = 33) or usual care (n = 32). Main Outcome Measures The primary outcome was severe deformational plagiocephaly assessed by plagiocephalometry. The secondary outcomes were positional preference, motor development, and cervical passive range of motion. Results Both groups were comparable at baseline. In the intervention group, the risk for severe deformational plagiocephaly was reduced by 46% at age 6 months (relative risk, 0.54; 95% confidence interval, 0.30-0.98) and 57% at age 12 months (0.43; 0.22-0.85). The numbers of infants with positional preference needed to treat were 3.85 and 3.13 at ages 6 and 12 months, respectively. No infant demonstrated positional preference at follow-up. Motor development was not significantly different between the intervention and usual care groups. Cervical passive range of motion was within the normal range at baseline and at follow-up. When infants were aged 6 months, parents in the intervention group demonstrated significantly more symmetry and less left orientation in nursing, positioning, and handling. Conclusion A 4-month standardized pediatric physical therapy program to treat positional preference significantly reduced the prevalence of severe deformational plagiocephaly compared with usual care.