The interest in this study was to establish comparative degradation behavior of lamivudine (3TC) and emtricitabine (FTC) under solution and solid state stress conditions. Structurally, the two drugs differ only in terms of additional fluorine at 5 position in FTC. Along with the known degradation products of both the drugs, one additional degradation product was observed in each case, which was characterized by mass spectrometry. Both the drugs degraded via the same route, but at a differential rate in acid, base and oxidative stress conditions. The variable rate of degradation in acid and base conditions was justified by the application of density functional theory (DFT).