BackgroundHelicobacter pylori infection (HPI) is extremely common in the world, particularly in less developed areas, but the primary causes of childhood HPI are unspecified. ObjectivesTo determine the influences of exposure to home environmental factors (HEFs), outdoor air pollutants (OAPs), and parental stress (PS), as well as their interactions on children’s HPI. MethodsWe implemented a retrospective cohort study with 8689 preschoolers from nine districts at Changsha, China, was conducted using questionnaires to collect data of health and HEFs. Temperature and OAPs data were collected from ten and eight monitoring stations, individually. Temperature and OAPs exposures were calculated for all home addresses using the inversed distance weighted (IDW) model. Multiple logistic regression analysis was carried out to determine the separate and combined impacts of HEFs, OAPs, and PS on HPI. ResultsChildren’s HPI was significantly associated with exposure to moisture-specific indoor allergens in one-year preceding conception, gestation, and first year, smoke-specific air pollution throughout life, and plant-specific allergens in previous year. Outdoor exposures to CO in the 7th-9th month before conception, as well as PM2.5 in the second trimester and previous year, were associated with HPI, with ORs (95% CIs) of 1.22 (1.05-1.41), 1.23 (1.03-1.46), and 1.33 (1.14-1.55). Parents’ socioeconomic and psychological stress indicators were positively related to HPI. High socioeconomic indicators and psychological stresses increased the roles of indoor renovation and moisture indicators as well as outdoor SO2, PM2.5 and O3 on children’s HPI over their entire lives. Parental psychological stress interacts with indoor renovation-specific air pollution, moisture- and plant-specific allergens, as well as outdoor traffic-related air pollution on HPI, during a critical time window in early life. ConclusionsIndoor and outdoor air pollutants, as well as allergens, separately and interactively exert important effects on childhood HPI, lending support to the “(pre-) fetal origin of HPI” hypothesis. ENVIRONMENTAL IMPLICATIONS•High parental socioeconomic status and psychological stress, including fatigue, headache, and inattention, significantly increased the risk of children’s Helicobacter pylori infection (HPI).•Indoor renovation-specific air pollution as well as moisture- and plant-specific allergens were related to an increased risk of childhood HPI.•Childhood HPI is strongly linked to exposure for outdoor traffic-specific air pollutants (CO and PM2.5) from preconception to the present.•High socioeconomic status and psychological stress amplified the effects of indoor renovation-specific air pollution and moisture-specific allergens on HPI.•Parental social stress and mental stress also increased the impacts of SO2 and PM2.5 and O3 on HPI, with a significant interaction.