We report off-label monthly use of high-dose of long-acting intramuscular cabotegravir/rilpivirine (CAB/RPV= 600mg/900mg) administered preconceptionally and throughout pregnancy to a young woman with perinatally-acquired HIV, hematologic and cardiovascular comorbidities and class III obesity. Therapeutic drug monitoring for CAB and RPV were performed throughout the pregnancy and postpartum. At 7 weeks gestation, the plasma CAB and RPV C trough were 16 (2.58 mg/L) and 9 (0.11 mg/L) times above the respective protein adjusted (PA)-IC 90. From 7 to 32 weeks of gestation, plasma CAB and RPV C trough decreased to 1.28 mg/L and to 0.08 mg/L), respectively, but remained above PA-IC 90 and Q1 C trough for both drugs. After receiving two high-dose CAB/RPV injections 7 weeks postpartum, the plasma CAB and RPV C trough were 4.02 mg/L and 0.19 mg/L, 56% and 74% higher than at 7 weeks of gestation. Despite a transient decrease in cabotegravir (50%) and rilpivirine (27%) concentrations, plasma exposures remained above therapeutic thresholds. Undetectable viral load (<20 copies/mL) was maintained preconceptionally and throughout the pregnancy. Higher CAB and RPV exposures did not result in adverse maternal, pregnancy or infant safety outcomes. At seven weeks postpartum, CAB/RPV dosing was switched to standard bimonthly schedule. At 33 weeks postpartum, the patient remained undetectable on standard CAB/RPV bimonthly dose, though subsequent pregnancies might require long-acting CAB/RPV dosing adjustments. Our case of empiric use of high-dose CAB/RPV with monthly injections and therapeutic drug monitoring during pregnancy in a complex patient with class III obesity provides novel insights into pharmacokinetics of long-acting CAB/RPV.