<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Differences in <jats:italic>Helicobacter pylori</jats:italic> protein expression have been related to the risk of severe gastric diseases. In Spain, a marked geographic pattern in gastric cancer mortality has long been reported. Objective: To characterize antibody reactivity patterns against 16 <jats:italic>H. pylori</jats:italic> proteins, by age, sex, and region of birth, in a large sample of the Spanish adult population.</jats:p></jats:sec><jats:sec><jats:title>Materials and Methods</jats:title><jats:p>Antibody reactivity was quantified by <jats:italic>H. pylori</jats:italic> multiplex serology in a sample from the control group of the multicase‐control study <jats:styled-content style="fixed-case">MCC</jats:styled-content>‐Spain. For this analysis, 2555 population‐based controls were included. Each participant was classified as seropositive or seronegative for each protein according to specific cutoffs. Overall <jats:italic>H. pylori</jats:italic> seroprevalence was defined as positivity against ≥4 proteins. Descriptive analyses by age, sex, and region of birth were performed for both seroprevalence and seroreactivity (continuous measure). Differences among groups were tested by logistic and linear regression models.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Overall <jats:italic>H. pylori</jats:italic> seroprevalence increased with age in both sexes. For ages 55‐74, seroprevalence was lower in women than in men (84% vs 92%, <jats:italic>P</jats:italic><.001). Region of birth explained 7% of the variability in seroprevalence. Among <jats:italic>H. pylori</jats:italic> seropositive subjects, proteins with the highest seroprevalence were Gro<jats:styled-content style="fixed-case">EL</jats:styled-content>, NapA, <jats:styled-content style="fixed-case">HP</jats:styled-content>231, and Omp. Seropositivity for most of the proteins increased or remained stable with age, rising mainly for CagA, Gro<jats:styled-content style="fixed-case">EL</jats:styled-content>, and HyuA in women. A clear cohort effect was not observed.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>This is the first study to describe the antibody patterns against 16 <jats:italic>H. pylori</jats:italic> proteins in the Spanish population. We found variability in the <jats:italic>H. pylori</jats:italic> antibody profiles according to both individual factors such as age and sex, and environmental factors such as the region of birth. The slightness of the reduction in seropositivity with decreasing age highlights the ongoing importance of this infection.</jats:p></jats:sec>