<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose</jats:title><jats:p>To investigate the relationship between the microstructure of CAD/CAM blocks and the quality of adhesion as function of the surface treatment and resin cement type.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>Two nano‐ceramic composite resin CAD/CAM blocks, Lava Ultimate (LU) and Cerasmart (CS), and two Leucite‐reinforced glass ceramic CAD/CAM IPS blocks, Empress<jats:sup>®</jats:sup> CAD (EM) and Initial<jats:sup>TM</jats:sup> LRF (IR), received either Hydrofluoric acid (HF) or sandblasting (SB) surface treatments. The blocks were then luted using two dual‐cure resin cements, LinkForce (LF) and Multilink Automix (ML) with their corresponding silanes, resulting in 16 study groups. The luted blocks were then thermal‐cycling (TC) for 5000 cycles and subjected to a microtensile bond strength (μTBS) test. Scanning electron microscopy (SEM) micrographs of the treated surfaces were analyzed using ImageJ software and XRD analyses were performed for the two ceramic blocks. The data obtained were submitted to Games‐Howell post‐hoc nonparametric test to compare combinations of groups or treatments and a linear mixed‐effects model for the factors surface treatment, block type, and resin cement, together with their first‐degree interactions (<jats:italic>α</jats:italic> = 0.05).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The lowest mean μTBS values were obtained with LU‐HF, whereas the highest mean μTBS values were obtained with CS regardless of resin cement type and surface treatment method. IR‐HF mean μTBS were significantly higher than IR‐SB, EM‐SB, and EM‐HF. Analysis using ImageJ software demonstrated significant differences in the density and pore size after HF surface treatment.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>The specific microstructure of each block material within the same family group impacted the micromechanical retention and the bonded interface strength.</jats:p></jats:sec>