A stability-indicating reverse phase ultra-performance liquid chromatography (RP-UPLC) method, developed for the simultaneous quantification of eight related compounds in the dosage forms of Emtricitabine, Tenofovir Disoproxil Fumarate and Efavirenz. Efficient chromatographic separation was achieved on an Acquity UPLC BEH Phenyl (2.1×100 mm, 1.7 m) column using mobile phase A (Buffer, 1.0 mL of TEA in 1000 mL of water pH adjusted to 4.0 ± 0.05 with diluted OPA) and mobile phase B (Buffer: Acetonitrile (20:80, v/v) in gradient mode with the flow rate of 0.5 mL/min and the peaks were monitored at 265 nm. In the developed method, the resolution of Emtricitabine, Tenofovir Disoproxil Fumarate, Efavirenz and related substances were found to be greater than 2.0. When the formulation samples are subjected to forced degradation the mass balance was found close to 99%. This method was validated in terms of limit of detection, limit of quantification, linearity, accuracy, precision and robustness as per ICH Q2R1. The test solutions were found to be stable in the diluent (Buffer: Methanol, 20:80 (v/v)) for 24 hours.