Oral diseases produce enormous productivity loss. However, epidemiological evidence of work stress and tooth loss is scarce. The aim of this study was to examine the association of work stress, according to effort–reward imbalance (ERI), with tooth loss. We conducted a cross-sectional study using data obtained between 2010 and 2011 in Japan. This study included 1,195 employees aged 25–50 years old (response rate=32%). The dependent variable was self-reported tooth loss (having or not). The independent variable was a dichotomized ERI ratio (>1.4 and ≤1.4). Age, sex, sociodemographic variables, work-related factors, and health-related variables were adjusted. Psychological distress was used as a potential mediator. We also examined an additive interaction between support from supervisors and ERI. The median age was 37, and 48% were women. After adjusting for the covariates, ERI was still associated with tooth loss (prevalence ratio=1.20 [95% confidence interval=1.01, 1.42] from Poisson regression models with a robust error variance). Psychological distress partially explained the association, and support from supervisors significantly attenuated the association. In conclusion, high ERI ratio was still associated with an increased risk of tooth loss among working adults.