Objective To evaluate the efficacy and safety of the modified sequential therapy with levofloxacin mesylate for curing Helicobacter pylori (H.pylori) infection in elderly patients. Methods A total of 120 elderly patients with benign H. pylori infection were included in the study, who were treated in Beijing Geriatric Hospital from January 2017 to June 2018. The patients were rando-mized into study group (sequential therapy) and control group (bismuth tetralogy). The study group received esomeprazole 20mg+amoxicillin 1000mg, twice a day for 5d and then esomeprazole 20mg+clarithromycin 500mg+levofloxacin mesylate 200mg, twice a day for 5d; the control group received esomeprazole 20mg+amoxicillin 1000mg+clarithromycin 500mg+bismuth potassium citrate 220mg, twice a day for 14d. Intention-to-treat (ITT) and per-protocol (PP) analysis were performed for the H.pylori eradication rate, and incidence of adverse reactions was compared between 2 groups. The cost-effectiveness analysis was performed to evaluate the economic benefits of two groups. SPSS statistics 17.0 was used for analysis, and t test or χ² test was used for comparison between 2 groups. Results In the study group, H.pylori was eradicated in 50 patients, with 6 cases being lost to follow-up; in the control group, H.pylori was eradicated in 46 patients with 5 being lost to follow-up and 4 failing to complete the treatment. ITT analysis showedan eradication rate of 83.3%(50/60) for the study group and 76.7%(46/60) for the control group, with no significant difference between 2 groups (χ²=1.944, P=0.378). PP analysis showed an eradication rate of 92.6%(50/54) for the study group and 90.2% (46/51) for the control group, with no significant difference between 2 groups (χ²=0.192, P=0.463). There were 7 adverse reactions (11.7%) but no serious adverse reactions in the study group, and 12(20.0%) adverse reactions and 4(6.7%) serious adverse reactions in the control group, with no significant difference in the incidence of adverse reactions (χ²=1.563, P=0.159) and severe adverse reactions (χ²=4.138, P=0.059) between 2 groups. One course of treatment costed 345.71RMB￥ in study group against 533.71RMB￥ in the control group. According to PP analysis, the cost-effectiveness ratio (C/E) of study group and control group were 373.3(345.71/92.6%) and 591.7(533.71/90.2%) with significant difference (P<0.05). ITT analysis showed a C/E of 415.0(345.71/83.3%) for the study group and 695.8(533.71/76.7%) for the control group also with significant difference (P<0.05). Conclusion The modified sequential therapy containing levofloxacin mesylate is effective in eradicating H. pylori in the elderly patients and can be one choice of therapy.