Studies of high-school science course sequences have been limited primarily to a small number of site-specific investigations comparing traditional science sequences (e.g., Biology-Chemistry-Physics: BCP) to various Physics First-influenced sequences (Physics-Chemistry-Biology: PCB). The present study summarizes a five-year program evaluation focused on the implementation of a modified-PCB sequence within a moderately large suburban high school, the findings of which highlight the importance of considering context-dependent support of PCB sequence implementations. This modified-PCB program transition was associated with increases in students' honors and Advanced Placement (AP) course enrollments, AP examination scores, understanding of the Nature of Science and experimentation, and self-reported affect toward themselves as learners and toward science in general. By contrast, no differential gains were observed in students' growth as measured by standardized tests (e.g., EXPLORE and ACT science scores). In addition to the program evaluation results associated with this course-sequence change, considerations are outlined related to the complexity of leading large-scale changes in secondary school science programs.