Although low birth weight premature infants and parents are at high risk for adverse health outcomes, there is a paucity of studies that test early NICU interventions with parents to prevent the development of negative parent-infant interaction trajectories and to reduce hospital length of stay. Our objective was to evaluate the efficacy of an educational-behavioral intervention program (ie, Creating Opportunities for Parent Empowerment) that was designed to enhance parent-infant interactions and parent mental health outcomes for the ultimate purpose of improving child developmental and behavior outcomes. A randomized, controlled trial was conducted with 260 families with preterm infants from 2001 to 2004 in 2 NICUs in the northeast United States. Parents completed self-administered instruments during hospitalization, within 7 days after infant discharge, and at 2 months' corrected age. Blinded observers rated parent-infant interactions in the NICU. All participants received 4 intervention sessions of audiotaped and written materials. Parents in the Creating Opportunities for Parent Empowerment program received information and behavioral activities about the appearance and behavioral characteristics of preterm infants and how best to parent them. The comparison intervention contained information regarding hospital services and policies. Parental stress, depression, anxiety, and beliefs; parent-infant interaction during the NICU stay; NICU length of stay; and total hospitalization were measured. Mothers in the Creating Opportunities for Parent Empowerment program reported significantly less stress in the NICU and less depression and anxiety at 2 months' corrected infant age than did comparison mothers. Blinded observers rated mothers and fathers in the Creating Opportunities for Parent Empowerment program as more positive in interactions with their infants. Mothers and fathers also reported stronger beliefs about their parental role and what behaviors and characteristics to expect of their infants during hospitalization. Infants in the Creating Opportunities for Parent Empowerment program had a 3.8-day shorter NICU length of stay (mean: 31.86 vs 35.63 days) and 3.9-day shorter total hospital length of stay (mean: 35.29 vs 39.19 days) than did comparison infants. A reproducible educational-behavioral intervention program for parents that commences early in the NICU can improve parent mental health outcomes, enhance parent-infant interaction, and reduce hospital length of stay.