There is still a lack of consensus concerning the recommended etching concentration, application time and type of silane when bonding lithium disilicate-reinforced glass ceramics manufactured by CAD/CAM. The purpose of this study was thus to conduct an in vitro study which investigates the influence of hydrofluoric acid (HF) concentration, etching time and silane type on the microtensile bond strength (μTBS) of lithium disilicate to resin composites. Thirty-nine IPS e.max CAD blocks were randomly divided between thirteen groups (n = 3). The variables were HF concentration (9.5 or 4.9%), etching time (20 or 60 s) and silane type (Bis-Silane, Monobond Plus and ESPE Sil Silane). The blocks were cut into beams, aged for 10,000 cycles in a thermocycler and submitted to tensile stress to determine μTBS. A control group featuring the Monobond Etch & Prime (MEP) agent that combines etching/silanisation into a simultaneous process was also added. This group was discarded from the analysis due to only having pre-test failures. The data were analysed using a three-way ANOVA (α = 0.05). The HF concentration, etching time and silane type significantly influenced μTBS (p < 0.001). Significant interactions between time and silane type (p = 0.004), HF concentration and silane type (p < 0.001) and among the three factors (p < 0.001) were noted. Etching lithium disilicate with 9.5% HF (60 s), followed by the application of Bis-Silane, resulted in the highest μTBS (16.6 ± 9.0 MPa). The highest concentration and etching time under study, combined with a two-part silane, resulted in the highest bond strength, while the application of MEP showed a complete pre-test failure.