Objective: The aim of this study is to evaluate the safety of cephalosporins, based on utilization and adverse drug events (ADEs). Methods: This is a retrospective study using data on cephalosporins, obtained from Yangtze River hospital drug information and the Wuhan adverse drug reactions monitoring center database, from January 2009 to December 2010, in 30 hospitals in China. Results: 22/44 (55%) cephalosporins were third-generation, which accounted for more than 50% of total expenditure. The top five cephalosporins (sorted by their defined daily doses) were cefodizime sodium, cefoperazone/sulbactam sodium, cefaclor, cefixime and cefmenoxime hydrochloride, which were used 182.93, 110.63, 109.09, 101.47 and 100.05 defined daily dose per 10,000 days, respectively. Third-generation cephalosporins were responsible for 747/1337 ADEs (55.87%). In particular, 208 episodes (15.56%) were associated with ceftriaxone. The most frequently reported damages were involved in the skin and its appendages (967, 68.92%). 603 (45.10%) were identified as definite in causality evaluation. Cefaclor was found to be safer than other cephalosporins, whereas ceftriaxone was found to be less safe. Conclusion: This retrospective evaluation demonstrated that overused and misused cephalosporins caused a relatively high incidence of ADEs. Therefore, surveillance should be strengthened successfully to optimize the rational use of cephalosporins.