Background <p>The relationship between long-term ambient air pollution exposure and socioeconomic status (SES) with rheumatic heart disease (RHD) has been rarely investigated.</p> Methods <p>We conducted a population-based cohort study involving approximately half a million participants based on UK Biobank. Long-term exposure to five air pollutants (PM_2.5, PM₁₀, PM_coarse, NO₂, and NO_x) was estimated by using land-use regression models. An overall SES indicator was derived by using latent class analysis based on household income, education level, and employment status. Cox proportional hazards models, together with mediation and interaction analyses were utilized to assess the associations of air pollution and SES with incident RHD.</p> Results <p>During a median follow-up of 13.6 years among 404,317 participants, a total of 7,944 incident RHD cases were identified. Higher SES was associated with a reduced risk of incident RHD (Medium vs. Low, HR = 0.77, 95% CI: 0.74–0.81; High vs. Low, HR = 0.65, 95% CI: 0.60–0.71; P for trend = 2.29 × 10–35). Statistically significant associations were also observed between incident RHD and PM_2.5 (HR: 1.10, 95% CI: 1.07–1.13, per IQR), PM₁₀ (HR: 1.04, 95% CI: 1.01–1.06, per IQR), NO₂ (HR: 1.09, 95% CI: 1.06–1.12, per IQR), and NO_x (HR: 1.07, 95% CI: 1.05–1.10, per IQR). Mediation analyses suggested that individual air pollutants statistically explained 1.2% to 10.6% of the association between SES and RHD risk. Furthermore, significant interactions were found between nitrogen oxides (NO₂ and NO_x) and SES on RHD risk. When considering joint effect, the HR was ~ 60% higher among individuals with high air pollution exposure and low SES compared to those with low air pollution exposure and high SES.</p> Conclusions <p>Long-term exposure to air pollution was associated with an increased risk of incident RHD. Notably, individuals with lower-SES exhibited greater susceptibility to the detrimental effects of air pollution exposure on RHD.</p>