Purpose: The purpose of this study was to evaluate resin infiltration (RI) technique's effects on the in vivo functional treatment of molar hypomineralization (MH)-affected permanent first molars (PFMs). Methods: Fifteen MH-affected PFMs were resin-infiltrated and evaluated for a three-month follow-up (FU). In vivo resin replicas were used for profilometric and scanning electron microscope (SEM) analysis of PFM surfaces; any variation of clinical aspect and dentin hypersensitivity was registered as: T0 equals baseline; T1 equals right after treatment; T2 equals oneweek follow-up; and T3, T4, and T5 equal one-, two-, and three-month FU. Results: At T0, MH-affected surfaces were rougher and more irregular than sound ones; at T1, resin-infiltrated surfaces were smoother while a progressive increase of superficial roughness was observed over time. Hypersensitivity improved at T1 and remained stable over time in severe MH cases. Conclusions: Resin infiltration seems to be a promising treatment, especially in managing severe molar hypomineralization cases for the evaluated follow-up.