Introduction: Biomimetic hydroxyapatite-based toothpastes have been investigated in recent years for their remineralizing activity on dental surfaces. The aim of the present study was to evaluate the efficacy of toothpaste containing biomimetic hydroxyapatite versus a 1450 pppm fluoride one in promoting the remineralization and desensitization of white spot lesions. Methods: 40 patients were randomly assigned to two different domiciliary oral hygiene treatments: toothpaste containing 1450 ppm of fluoride (control group) and toothpaste containing biomimetic hydroxyapatite (experimental group). Dental sensitivity/pain and dental erosion were assessed at baseline and after 15, 30, and 90 days using the following indexes: Schiff Air Index (SAI), Visual Analogue Scale (VAS), and Basic Erosive Wear Examination (BEWE). Results: Data were submitted for statistical analysis. SAI significantly decreased after 3 months (T3) of treatment only in the Trial group (p < 0.05). VAS values significantly decreased at T2 in the trial group (p < 0.05) with a further significant reduction at T3 (p < 0.05). BEWE scores did not significantly vary during the follow up neither in the trial nor in the control group. Conclusions: The hydroxyapatite-based toothpaste tested caused a reduction of hypersensitivity/pain values higher than conventional fluoride toothpaste.