ObjectivesThis study aimed to evaluate how self-etching/universal dental adhesive systems (DASs) with differing compositions interact with sound (S), post-radiotherapy (irradiated; I), and artificially eroded (E) dentin in terms of bonding properties. Methods: The DASs tested were Adper Scotchbond Multipurpose (MP; control), Clearfil SE Bond (SE), FL Bond II (FL), Adper Single Bond Universal (SU) and BeautiBond Xtreme (BX). They were analyzed for initial and 6-month microtensile bond strength (µTBS, n = 12), mode of failure (40 x), scanning electron microscopy (SEM), surface wettability (W, n = 10), and degree of conversion (DC, n = 3) via Fourier-transform infrared spectroscopy (FTIR). Normal and homogeneous distribution of the data allowed their analyses through ANOVA and Tukey tests (p < 0.05). Results: All DASs except BX exhibited higher µTBS for S decreasing for I and E. BX demonstrated the greatest stability among the altered substrates. FL showed the most hydrophobic properties, likely due to its bioactive components. Universal DASs achieved higher DC, regardless of composition. Conclusions: HEMA-free formulation combined with carboxylic and phosphoric acids in BX, achieved the most stable performance for altered substrates. Clinical SignificanceSince radiotherapy and erosion affect dentin, their characteristics compromise adhesive performance and impair the achievement of durable and satisfactory restorations. The use of universal adhesives less dependent on calcium seems less susceptible to hydrolytic degradation and may be a promising option for maintaining adhesive stability over time.