This study investigated the effect of intraoral humidity on microtensile bond strength (μTBS) to dentin of two universal adhesives applied in self-etch (SE) mode. Forty extracted human molars were selected for this study. Dentin specimens were allocated into four groups, standardized and then bonded with two commercial multimode adhesives, according to two humidity conditions (50% relative humidity (RH) and 90% RH). Following composite resin build-up and 24 h of water storage, the μTBS of the bonded interface was analyzed. The 50% RH was higher for Scotchbond Universal (SBU) than Prime&Bond Universal (PBU), while for 90% RH, SBU had significantly lower values than PBU. With PBU, the mean bond strength was not significantly different between both humidity settings tested (p > 0.05), while for SBU, the mean bond strength was significantly different between both conditions tested (p < 0.05); μTBS was significantly higher for 50% RH than for the other group. Within the limitation of this in vitro study, it can be concluded that: 1) the bonding performance of adhesives systems depends on the humidity settings; 2) increased RH exerts a detrimental effect on the bond strength of 2-hydroxyethyl methacrylate (HEMA)-containing adhesive tested. However, this phenomenon was not observed for HEMA-free adhesive tested; 3) further research in this area is needed to investigate different adhesive systems, temperatures and humidity settings.