Novel RP-HPLC Method Development and Validation for Simultaneous Quantification of Rilpivirine and Cabotegravir in Pharmaceutical Formulations by Isocratic Separation using THERMO C18 Column. This method employs OPA-Methanol (50:50, pH 3.5) as the mobile phase at a flow rate of 1.0 mL/min, and UV detection at 219 nm. Retention times were 1.712 and 2.295 minutes for Rilpivirine and Cabotegravir, respectively. This method exhibited linearity in the concentration range of 50 µg/ml to 150 µg/ml for both drugs, with correlation coefficients of 0.9999. Limits of detection (LOD) and quantification (LOQ) were determined as 1.554 and 5.180 µg/ml for Rilpivirine, and 1.011 and 3.370 µg/ml for Cabotegravir. Excellent percentage recoveries of 100% for both analytes highlight the high accuracy of the proposed method. Specificity was confirmed through the correlation of retention times between standard and sample, ensuring interference-free determination of analytes in tablet dosage forms. The method underwent extensive validation following ICH guidelines, demonstrating robustness in terms of Linearity, Accuracy, Precision, Specificity, and Robustness.