Objective To explore occupational exposure of nurses and to compare the differences between infectious disease hospitals and general hospitals, so as to provide reference for targeted interventions. Methods A self-designed questionnaire relating occupational exposure and protection management was used to investigate 19,588 nurses of 306 hospitals in 31 provinces (municipalities and autonomous regions) in China. Results Greater than ninety percent (93.29%) of the participants knew standard prevention and 95.79% of them knew how to manage after hepatitis B exposure, showing no significant differences between infectious disease hospitals and general hospitals (P>0.05 for both). The percentages of nurses who could correctly perform prophylaxis after exposure to AIDS and hepatitis C were significantly higher in infectious disease hospitals than those in general hospitals (P<0.01 for both). The prevalence of occupational exposure among nurses was 51.86% with a reporting rate of 66.00%, and occupational exposure commonly occurred on the hand(97.75%) due to inappropriate disposal of needlestick (62.61%), showing significant poor performance in general hospitals compared with infectious disease hospitals（P<0.01 for all）. The rate of testing within 24 hours of exposure was 84.04%, and the rate of receiving follow-up and compensation was 87.72% and 70.81% respectively, indicating no significant difference between the two types of hospitals (P>0.05). Payment for testing was medical insurance or self-financed. Nearly one-third of the hospitals (33.02%) had clear compensation mechanism for occupational exposure, with the infectious disease hospitals superior to general hospitals (P<0.01). Conclusion The findings show high prevalence and low reporting of occupational exposure among nursing staff and more exposures to needlestick injuries. Knowledge, risk assessment, support and guarantee should be enhanced, particularly in general hospitals. Managers of all levels of hospitals should pay great attention to and take targeted interventions to ensure nurses′ occupational safety.