Objective To study the distribution and drug resistance of pathogens causing hospital-acquired pneumonia (HAP) and explore the related risk factors, so as to provide valuable clinical reference for prevention and treatment of HAP. Methods A case-control study was conducted in a 3700-bed tertiary hospital. Nosocomial infections reported from January 2014 to December 2014 were investigated. A total of 419 inpatients with HAP were enrolled in as a study group, and 419 inpatients without nosocomial infection in the same period and department, with same gender, underlying diseases, and same age, were chosen as a control group. Risk factors of HAP, distribution and drug resistance of pathogens of HAP were analyzed. Results The incidence rate of HAP was 0.62% and the mortality rate was 19.81%. Multivariate analysis identified chronic lung diseases, admission in ICU, two or more kinds of antibiotics used, hospitalization time≥5 days, cerebrovascular disease, and mechanical ventilation were significant risk factors. Totally 492 strains of pathogens were isolated, including 319 strains of gram-negative bacteria, 61 strains of gram-positive bacteria, 112 strains of fungi.Acinetobacter baumannii,Klebsiella pneumonia,Candida albicans,Pseudomonas aeruginosa,Candida glabrata ranked the top five predominant pathogens. Drug resistance rates ofAcinetobacter baumannii to commonly used antibiotics were higher than 75%. Drug resistance rates ofKlebsiella pneumoniae to piperacillin and third-generation cephalosporin were higher than 50%. Conclusions HAP prevails in patients with hospitalization time≥5 days, admission in ICU, cerebrovascular diseases, two or more antibiotics combined used, chronic lung diseases, and mechanicalventilation. It is associated with increased length of hospital stay, decreased quality of life, and elevated morbidity and mortality. The main pathogens of HAP are Gram-negatives.Acinetobacter baumannii andKlebsiella pneumoniae are resistant to the common antibiotics in different degree.