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Concerns have been raised about the potential association between selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs) and the risk of abnormal uterine bleeding (AUB), which may be influenced by the affinity of SSRIs/SNRIs for serotonin transporter. Thus, we assessed whether SSRIs/SNRIs with high-affinity for serotonin transporter are associated with AUB compared to SSRIs/SNRIs with low-affinity in non-pregnant women. Using the UK Clinical Practice Research Datalink, we identified a cohort of women aged 15–24 years, newly prescribed a high- or low-affinity SSRI/SNRI between 1990 and 2019. Confounding was addressed using standardized morbidity ratio weighting. We used weighted Cox proportional hazards models to estimate the hazard ratio (HR) and 95 % confidence interval (CI) of AUB associated with high-affinity compared with low-affinity SSRIs/SNRIs. We assessed the risk of anemia as a secondary outcome. The cohort included 156,307 users of high-affinity SSRIs/SNRIs and 102,631 users of low-affinity SSRIs/SNRIs. High-affinity SSRIs/SNRIs were not associated with an increased risk of AUB compared with low-affinity SSRIs/SNRIs (incidence rates: 46.3 versus 42.4 per 1000 person-years, respectively; HR 1.01, 95 % CI 0.93–1.09). Duration of use, age, and comorbidities did not modify the risk. However, high-affinity SSRIs/SNRIs were associated with an increased risk of anemia (HR 1.29, 95 % CI 1.04–1.61) compared with low-affinity SSRIs/SNRIs. Residual confounding may still be present. The risk of AUB did not differ between high- and low-affinity SSRIs/SNRIs. However, the potential risk of anemia suggests the need for monitoring and further investigation of the risk of AUB with these medications. • SSRIs/SNRIs affinity to receptors may influence risk of abnormal uterine bleeding. • Strong-affinity SSRIs/SNRIs were not associated with risk of abnormal uterine bleeding. • Strong-affinity SSRIs/SNRIs were associated with a higher risk of anemia. • Monitoring of these potential side effects may be considered when prescribing SSRIs/SNRIs. [ABSTRACT FROM AUTHOR]