The aims of this study were to demonstrate the trends in seropositivity and the eradication therapy rate for Helicobacter pylori (H. pylori) over an 18-year period in an asymptomatic Korean population and to explore the factors associated with H. pylori seropositivity and its eradication therapy. In total, 23,770 subjects (aged 17-97 years) from a health examination center participated in this cross-sectional study from January 2016 to June 2017. Questionnaires that included questions about the participants' H. pylori eradication therapy history were collected, and anti-H. pylori IgG antibodies were measured. Among the eligible subjects, the seroprevalence of H. pylori infection was 41.5%. The H. pylori eradication therapy rate increased continuously from 2005 (13.9%) to 2011 (19.3%) and then increased again until the first half of 2017 (23.5%) (P < 0.001). After exclusion of subjects with a history of gastric surgery, gastric cancer, H. pylori eradication therapy, or gastric symptoms, H. pylori seropositivity was 43.9% in 16,885 subjects, which was significantly lower than the seropositivities in 1998 (66.9%), 2005 (59.6%), and 2011 (54.4%). The risk factors associated with H. pylori seropositivity according to multivariable analysis were male sex (odds ratio (OR) 1.34, 95% confidence interval (CI): 1.23-1.46), medium educational level (OR 1.17, 95% CI: 1.05-1.31), medium household income level (OR 1.10, 95% CI: 1.03-1.19), and age of 60-69 years (OR 8.78, 95% CI: 6.41-11.85). The observed downward trend in H. pylori seroprevalence and increase in H. pylori eradication over the 18-year period will affect upper gastrointestinal disorders in South Korea.