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Abstract A complete understanding and good adherence are crucial for successful Helicobacter pylori eradication. Proper frequency of reminders might be helpful to both doctors and patients to maintain adherence during treatment. The study was to evaluate the influence of an intensive follow‐up system based on a clinical database on H. pylori eradication therapy. A total of 196 eligible patients were equally and randomly divided into an intensive follow‐up group and a control group. Both groups were administered bismuth‐containing quadruple therapy for 14 days. Patients in the intensive follow‐up group were informed of pre‐treatment, including the duration and potential adverse events. Subsequently, they received telephone follow‐ups on days 3 and 14 and 3 days before the urea breath test (UBT). The time points were automatically reminded by a follow‐up system in the established clinical database. The control group was only informed of pre‐treatment information. UBT was performed 4 weeks after treatment in both groups to assess the presence of H. pylori. The eradication rate, patient compliance, and adverse events were calculated and compared. The H. pylori eradication rates of the intensive follow‐up and control groups were 94.7% (90/95, 95% CI: 90%–99%) and 92.9% (78/84, 95% CI: 87%–98%), respectively, by PP analysis (p = 0.601), and 91.8% (90/98, 95% CI: 86%–97%) and 81.6% (80/98, 95% CI: 74%–89%) by ITT analysis (p = 0.035). Adverse events occurred in 9 intensive follow‐up group patients and 12 in the control group. Adherence was 96.9% (95/98) in the intensive follow‐up group and 85.7% (84/98) in the control group. Semi‐automatic intensive follow‐up contributed to a higher eradication rate and adherence to H. pylori treatment.