BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have been associated with increased risk of upper gastrointestinal bleeding (UGIB) in older patients, but little is known about the risk associated with individual SSRI drugs and doses. METHODS: We conducted a nested case-control study within a cohort of 9,295 patients aged ≥65 years treated with SSRIs from 2000 to 2013 using claims data of a universal health insurance in Taiwan. Incident cases of UGIB during follow-up period were identified and matched with three control subjects for age, sex, and follow-up duration. Conditional logistic regression was used to estimate odds ratio (OR) of UGIB associated with use of individual SSRI drugs and cumulative dose. RESULTS: UGIB risk increased with the increasing cumulative doses of SSRIs (adjusted OR: 1.28, 95% confidence interval [CI]: 1.02–1.62 for the highest vs. the lowest tertile). Compared with users of other SSRIs, Fluoxetine users were at had an increased risk of UGIB (adjusted OR: 1.25, 95% CI: 1.03–1.50), whereas paroxetine users had 29% decreased odds (95% CI: 0.56–0.91). A dose-response manner was observed between fluoxetine use and UGIB (adjusted OR [95% CI] for tertiles of cumulative dose vs. use of other SSRI classes: tertile 1, 1.04 [0.78-1.39]; tertile 2, 1.25 [0.96-1.63]; tertile 3, 1.44 [1.11–1.87]). The increased risk was only observed among current fluoxetine users. CONCLUSIONS: Among older adults treated with SSRIs, fluoxetine therapy was associated with increased risk of UGIB in a dose-response manner. Careful considerations in treatment dosage are needed when providing care to older people.