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Dipeptidyl peptidase‐4 inhibitors (DPP‐4i) interact with sulfonylureas to increase their risk of hypoglycemia. Our population‐based study assessed whether intraclass pharmacologic heterogeneity among sulfonylureas (long‐ vs. short‐acting) and DPP‐4i (peptidomimetic vs. non‐peptidomimetic) modifies this interaction. We conducted a cohort study using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data. We assembled a cohort of patients initiating sulfonylureas (2007–2020). Using a time‐varying exposure definition, we assessed the risk of severe hypoglycemia (hospitalization with or death due to hypoglycemia) associated with (i) concomitant use of long‐acting sulfonylureas (glimepiride and glibenclamide) with DPP‐4i compared with concomitant use of short‐acting sulfonylureas (gliclazide and glipizide) with DPP‐4i; and (ii) concomitant use of sulfonylureas with peptidomimetic DPP‐4i (saxagliptin and vildagliptin) compared with concomitant use of sulfonylureas with non‐peptidomimetic DPP‐4i (sitagliptin, linagliptin, and alogliptin). Time‐dependent Cox models estimated confounder‐adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Our cohort included 196,138 sulfonylurea initiators. During a median follow‐up of 6 years, 8,576 events of severe hypoglycemia occurred. Compared with concomitant use of short‐acting sulfonylureas with DPP‐4i, concomitant use of long‐acting sulfonylureas with DPP‐4i was not associated with the risk of severe hypoglycemia (adjusted HR: 0.87, 95% CI: 0.65–1.16). Compared with concomitant use of sulfonylureas with non‐peptidomimetic DPP‐4i, concomitant use of sulfonylureas with peptidomimetic DPP‐4i was also not associated with the risk of severe hypoglycemia (HR: 0.96, 95% CI: 0.76–1.22). Intra‐class pharmacologic heterogeneity did not modify the association between concomitant use of sulfonylureas (short‐ vs. long‐acting) and DPP‐4i (peptidomimetic vs. non‐peptidomimetic) and the risk of severe hypoglycemia.