With the rising incidence of HIV/AIDS in China, nurses will increasingly be caring for patients with HIV/AIDS. Thus, it is necessary that they have enough knowledge to reduce the risk of occupationally acquired HIV infection and that they change their attitude to care for HIV/AIDS patients. The objective of this study is to explore the relationship between student nurses' HIV/AIDS knowledge and their attitude using a structural equation model (SEM). A cross-sectional survey was conducted in January 2008 among 528 student nurses at the technical secondary school of the China Medical University. An SEM is proposed to determine the direction and magnitude of the interdependent effects between the latent factors. The SEM was built using LISREL version 8.5. The measurement properties of the latent factors underlying the questionnaire were based on a confirmatory factor analysis (CFA). Our results as following, HIV/AIDS knowledge and attitude may be measured by seven underlying constructs, namely, preventive knowledge, knowledge of transmission routes, specialty knowledge, knowledge of nontransmission routes, positive attitude toward HIV/AIDS, negative attitude toward HIV/AIDS, and occupational attitude. The SEM fits the data well. The interdependent relationships between these constructs identified the factors of preventive knowledge, specialty knowledge, and attitude toward HIV/AIDS as having both direct and indirect effects on occupational attitude. In conclusions, our results represent an initial effort to assess the relationship between student nurses' HIV/AIDS knowledge and their attitude toward the disease. CFA and SEM analysis have demonstrated their usefulness in evaluating multifactor complex constructs.