Abstract: Objective To investigate the clinical features and drug resistance of neonatal purulent meningitis caused by Escherichia coli. Methods The clinical data of 46 neonates diagnosed with purulent meningitis caused by Escherichia coli were retrospectively analyzed from June 2004 to June 2014. The neonates were divided into community acquired infection group and nosocomial infection group, or early group (from June 2004 to May 2009) and late group (from 2009 June to June 2014). Result Fever, hypothermia, lethargy, poor feeding, tachypnea, and tachycardia were common clinical manifestations in all neonates. The detection rate of ESBLs was significantly higher in nosocomial infection group than that in community acquired infection group (P < 0.05), and also was significantly higher in the late group than that in the early group (P < 0.05). The rates of resistance to commonly used cephalosporins were significantly higher in nosocomial infection group than those in community acquired infection group. The rates of resistance to commonly used penicillin and cephalosporin were significantly higher in the late group than those in the early group (P < 0.05). Conclusions The clinical manifestations of neonatal purulent meningitis caused by Escherichia coli are not typical. The drug resistance rates of ESBLs to penicilins and cephalosporins are increasing recently. Nosocomial infection is the risk factor for ESBLs.