Objective To analyze the influencing factors and structure of hospitalization expense of patients with 5 major diseases and explore feasible measures of controlling the hospitalization expense. Methods The new grey relational analysis was adopted and 5 components of hospitalization expense of 2 184 patients with 5 major diseases in 2013 were quantitatively analyzed by SPSS 19.0 and Excel 2010. The relationship of each factor and hospitalization expense was calculated and the major influencing factor of the expense was identified. Results The results of relationship calculation of new grey relational analysis showed that the drug cost was the most important influencing factor of hospitalization expense of patients with 5 major diseases and the treatment cost was the second important influencing factor. The influence of other costs such as examination costs and costs for traditional Chinese medicine was relatively less. Conclusion The results of new grey relational analysis is close to the reality and the calculation is simple. It is suitable for analyzing the influencing factors of hospitalization expense of patients with major diseases.