Objectives: The aim of this study was to investigate the effects exerted by the acidulated fluoride gel on stainless steel and nickel-titanium (Ni-Ti) orthodontic wires. Materials and Methods: Sixty stainless steel and Ni-Ti orthodontic archwires were distributed into forty archwires used for in vitro study and twenty for in situ study. Fluoride was applied for 1 h in the in vitro experiment while it was applied for 5 min in the in situ experiment. The friction resistance of all wires with ceramic brackets before/after topical fluoride application was measured using a universal testing machine at 1 min intervals of moving wire. Moreover, surface properties of the tested wires before/after fluoride application and before/after friction test were examined by a scanning electron microscope (SEM). Dunnett′s t-test was used to compare frictional resistance of as-received stainless steel wires and Ni-Ti wires to the wires treated by fluoride in vitro and in situ (P < 0.05). Two-way ANOVA was used to compare the effect of fluoride application and type of wire on friction resistance in vitro and in situ (P < 0.05). Results: Ni-Ti wires recorded significantly high friction resistance after fluoride application when compared to stainless steel wires in vitro, P < 0.05. Fluoride application did not significantly affect the friction resistance of the tested wires in situ, P < 0.05. SEM observation revealed deterioration of the surface texture of the Ni-Ti wires after fluoride application in vitro and in situ. Conclusions: The in vitro fluoride application caused an increase in friction resistance of Ni-Ti wires when compared to stainless steel wires. In vitro and in situ fluoride application caused deterioration in surface properties of Ni-Ti wires.