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Background: Post-placement menstrual bleeding pattern changes with intrauterine contraceptives (IUCs), including levonorgestrel-releasing intrauterine systems (LNG-IUS), can be a reason for avoidance or early discontinuation. Prostaglandins play an important role in menstrual bleeding and pain. The key drivers of prostaglandin synthesis are cyclooxygenase (COX) enzymes, which are inhibited by non-steroidal anti-inflammatory drugs. In this study, we report the findings from pharmacokinetic (PK) analyses undertaken with an LNG-IUS (LNG-IUS 8) modified with an additional reservoir containing indomethacin (IND). Methods: The IND/LNG-IUS 8 is a proof-of-concept device studied in a phase II proof-of-concept/dose-finding study. IND/LNG-IUS 8 contains the same LNG content as the unmodified LNG-IUS 8 (13.5 mg) but was prepared with three different IND doses (low, 6.5 mg; middle, 12.5 mg; and high, 15.4 mg), resulting in different daily release rates. Overall, 174 healthy, premenopausal women were randomized to one of the four treatment arms (low-, middle-, high-dose IND/LNG-IUS 8 or LNG-IUS 8). Initial and residual IND and LNG content were collected and the amount of IND and LNG released in vivo over the period of use was calculated. A subset of 62 participants underwent dense blood sampling for PK analysis. Concentrations of IND and LNG in plasma were determined by validated liquid chromatography-tandem mass spectrometry methods and plotted over time. Descriptive statistics were calculated for plasma drug concentrations and PK parameters. Results: High-dose IND/LNG-IUS 8 initially released much higher levels of IND than expected based on in vitro release data, followed by a steep decline, with the reservoir emptied by 4.5 months. Middle- and low-dose IND/LNG-IUS 8 demonstrated steady sustained release of IND over time, emptying after 7.4 and 8.4 months, respectively. Peak plasma concentrations of IND for low- and middle-dose IND/LNG-IUS 8 remained below the 20% maximal inhibitory concentration (IC20) values for COX enzymes. The average daily IND release rate in vivo was 49 µg/day for low-dose and 112 µg/day for middle-dose IND/LNG-IUS 8. The IND release rate profile and IND plasma concentrations in vitro both decreased steadily over time with low- and middle-dose IND/LNG-IUS 8. The LNG release rate profile was comparable for all IND/LNG-IUS 8 dose groups and LNG-IUS 8. Conclusion: This PK study demonstrates that two different drugs can be released at different rates from an IUS designed with two drug reservoirs. Inclusion of IND does not impact the LNG PK profile. Low- and middle-dose IND/LNG-IUS 8 were associated with a systemic IND exposure that should preclude the occurrence of adverse events typically observed after oral IND dosing. Study Registration: ClinicalTrials.gov identifier number: NCT03562624 [ABSTRACT FROM AUTHOR]