We report two cases of normoglycemic people with HIV well-controlled by antiretroviral therapy who were switched to a dual long-acting therapy consisting of cabotegravir (CAB), an integrase strand transfer inhibitor, and rilpivirine (RIL), a non-nucleoside analog reverse transcriptase inhibitor, administred intramuscularly once a month. Both cases developed shortly acute severe hyperglycemia with ketoacidosis or insulinopenia requiring intravenous insulin therapy. Anti-pancreatic autoantibodies were absent. The hyperglycemic episode resumed after stopping CAB/RIL and/or initiating metformin. To our knowledge these are the first reported cases of severe CAB/RIL-induced hyperglycemia. Up to now, long-acting CAB/RIL has not been associated with metabolic outcomes. These cases serve as a warning to clinicians to monitor glycemia when initiating long-acting CAB/RIL therapy.