Aim: To study the effects of a prophylactic fluoride regimen on the mechanical properties of nickel-titanium (Ni-Ti) archwires under clinical conditions. Method: The unloading properties of 100 Ni-Ti wires were tested using a three-point bending test at five deflections (0.5 mm, 1.0 mm, 2.0 mm. 3.0 mm, and 3.1 mm). Sixty-six 0.016 3 0.022-inch Ni-Ti wires were tested after being used intraorally for 6 weeks using two protocols. Thirty-three wires were evaluated after the use of fluoride-containing Crest toothpaste (sodium fluoride 0.243%, 0.15% w/v fluoride ion) and Equate fluoride rinse (sodium fluoride 0.05%, fluoride ion 0.0226%). Another 33 wires were examined after a nonfluoridated natural toothpaste (Tom’s of Maine; calcium carbonate, xylitol, myrrh, propolis, sodium lauryl sulfate, carrageenan, spearmint and peppermint oils, glycerin, and water) was used. Another 34 Ni-Ti wires served as a control; they were tested as received. Statistical analyses were carried out with a linear-mixed model (analysis of variance [ANOVA]). Results: Force degradation occurred within both groups of intraorally used wires but not in the unused archwires. When compared to unexposed wires, those with fluoride exposure exhibited slightly higher force degradation at 3.1 and 3.0 mm deflection, but they displayed less force degradation at 0.5 and 1.0 mm deflection. Conclusions: Topical fluoride regimens decreased the unloading property of Ni-Ti wires at higher deflections but increased it at lower deflections. World J Orthod 2010;11:135–141.