Purpose: Many children begin school with limited vocabularies, placing them at a high risk of academic difficulties. The goal of this study was to examine the effects of a vocabulary intervention program, "Story Friends," designed to improve vocabulary knowledge of at-risk preschool children. Method: Twenty-four early-childhood classrooms were enrolled in a cluster-randomized design to evaluate the effects of a revised "Story Friends" curriculum. In each classroom, three to four preschoolers were identified as having poor language abilities, for a total of 84 participants. In treatment classrooms, explicit vocabulary instruction was embedded in prerecorded storybooks and opportunities for review and practice of target vocabulary were integrated into classroom and home practice activities. In comparison classrooms, prerecorded storybooks included target vocabulary, but without explicit instruction, and classroom and home strategies focused on general language enrichment strategies without specifying vocabulary targets to teach. Intervention activities took place over 13 weeks, and 36 challenging, academically relevant vocabulary words were targeted. Results: Children in the treatment classrooms learned significantly more words than children in the comparison classrooms, who learned few target words based on exposure. Large effect sizes (mean d = 1.83) were evident as the treatment group averaged 42% vocabulary knowledge versus 11% in the comparison group, despite a gradual decline in vocabulary learning by the treatment group over the school year. Conclusions: Findings indicate that a carefully designed vocabulary intervention can produce substantial gains in children's vocabulary knowledge. The "Story Friends" program is feasible for delivery in early childhood classrooms and effective in teaching challenging vocabulary to high-risk preschoolers. [This is the online version of an article published in "Journal of Speech, Language, and Hearing Research." For the final published version of this article, see EJ1281464.]