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Objective: To examine the effectiveness of an interdisciplinary, discovery-oriented teaching unit designed to provide science and health information about HIV from the perspective of viral biology, population statistics and epidemiology. Design: Single group pre- and post-curriculum pilot study. Setting: Fifteen middle and high school classrooms recruited from districts in and around a large, diverse, urban area in the mid-southern USA. Method: Science educators, clinicians, virologists and biologists collaborated to develop a set of five activities intended to increase content knowledge related to HIV, while developing students’ science-related skills in the context of an authentic, relevant example. The activities were piloted with six hundred and twenty-four 12- to 18-year-old students. Multiple-choice pre- and post-tests were used to assess changes in students’ knowledge, and teacher evaluations were used to gauge appropriateness of content, ease of activity implementation and teacher perceptions of student skill development, learning and engagement. Results: Student pre- and post-tests and teacher post-evaluations indicated that the curriculum was effective in increasing content knowledge for students across all age ranges, with 13- to 14-year-old, grade 8 students achieving the greatest knowledge gains. Teacher-reported information also suggested that students were able to apply relevant skills to their interpretation of authentic data related to the incidence and transmission of HIV infection around the world. Conclusion: The developed activities have the potential to provide timely, relevant information to students while strengthening science-related content knowledge and skills as well as health literacy.