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This study assesses the ability of an online sexuality education (OSE) module (‘You and Me’) to enhance sexual and reproductive health (SRH) knowledge and attitudes among 10th-grade vocational high school students in China. We conducted a cluster randomized controlled trial, randomizing 29 vocational high schools to (i) receiving the module (intervention) or (ii) not receiving the module (control). Students completed a baseline questionnaire, then completed the module within 8 weeks and then completed a follow-up questionnaire within the following 2 weeks. We assessed the differences in intervention effects using hierarchical linear modeling. No significant differences between intervention and control groups were found for knowledge and attitude scores at baseline among the 2985 students included in the analyses. For the intervention group at follow-up, we observed significant improvements in SRH knowledge scores of approximately 20% for boys and girls although girls responded to the module with larger knowledge gains than boys. At follow-up, intervention group students also had higher SRH attitude scores toward views that are more contemporary than the control group. In addition, girls held more contemporary attitudes than boys. The comprehensive OSE module assessed is effective in improving SRH knowledge, and attitude among Chinese vocational high school students after the module is completed.