Objective: Clinical treatment for blaKPC-positive Klebsiella pneumoniae isolates is challenging because the recommended antibiotic options are limited and are extraordinarily expensive. This study aimed to explore a new therapy for infection caused by KPC-producing K. pneumoniae. Methods: Patients with blaKPC-positive K. pneumoniae infection, were prospectively screened and were categorised into two groups: patients in the study group received a combination-based therapy of cefepime and amoxicillin/clavulanic acid and the control group received tigecycline-based therapy. The pathogen clearance rate, 28-day mortality and cost of the antibiotic treatment were compared between the two groups. Moreover, the checkerboard microdilution method was performed to determine the synergy between cefepime and amoxicillin/clavulanic acid in vitro. Results: Twenty-six and 25 cases were enrolled in the study and control groups. The mortality and the overall pathogen clearance rate showed no significant differences (P=0.311 and P=0.447). Both the total cost and the portion of the cost not covered by insurance were higher for the control group compared to the study group (both P<0.001). Consistently, synergy (65.4%) and partial synergy (26.9%) were the main effects. Conclusions: In contrast to the currently recommended tigecycline-based therapy, cefepime and amoxicillin/clavulanic acid combination was an effective and economical option to KPC-KP infection in China.