Objective To investigate the clinical effectiveness and adverse event of preventive medicine for severe acute respiratory syndrome (SARS), and provide clinical data for designing prospective clinical trial. Method Retrospective study on medical staffs, that were exposed to SARS patients, was conducted in two main SARS designated hospitals to obtain information such as SARS exposure risk and preventive measures (medical and others). According to the type of preventive medicine, they were assigned to earthworm’s nucleases and protease (ENP) group, interferon group and blank control group respectively. Exposure risk, suspected sub-clinical infection rate and adverse event rate were compared between the three groups. Results Non-medical preventive measures used in each group were consistent, but the exposure intensity to risk factors between groups was statistically different, which biased the evaluation of clinical effectiveness of preventive medicine. The rate of suspected sub-clinical infection in earthworm’s nucleases and protease (ENP) group, interferon group and control group were 4.5%, 4.5%, and 9.9% (Pgt;0.05), respectively; and adverse event rate were 19.6%, 13.6% (Pgt;0.05), and 0%, respectively. Conclusions Suspected sub2clinical infection rate in ENP group, interferon (INF) group were lower than that in control group, which indicated that these two medicines might be effective in preventing SARS. Adverse event rate in ENP group was similar to that of interferon group, and the symptoms were mild in both groups, which was in accordance with the result of in vitro experiments. ENP spray is a kind of biological preparation; further purification may reduce its adverse event rate. However, because there had excessive confounding factors, especially because of the unequal of exposure risk between three groups, the results of this study can only provide insights to design prospective clinical trial in the future.