Objective: To evaluate the efficacy of in-office tooth bleaching following application of either ozone (O3) or hydrogen peroxide (H2O2). Method and Materials: 32 participants were randomly distributed into two groups (n = 16 each). Participants' maxillary anterior teeth were treated with ozone (produced via a healOzone X4 device; Curozone) for 60 seconds in Group 1, or with 38% H2O2 for 20 minutes in Group 2. Tooth shades were evaluated by means of a colorimeter (CR-400, Minolta) measuring Vita classic shades in addition to L*a*b* shade values before and following bleaching in each group. A visual analog scale was used to evaluate tooth sensitivity before and after bleaching. Statistically significant differences were identified at P .05. Results: Teeth obtained lighter shades (increased L* and reduced a* and b* values) following bleaching in both groups (P .001). Both groups revealed comparable bleaching outcomes (P > .05). However, bleaching with ozone did not result in tooth sensitivity, whilst using H2O2 was accompanied with significantly increased bleaching sensitivity (P .001). Conclusion: Similar bleaching outcomes and lighter tooth shades (both for Vita shades and L*a*b* values) were obtained following in-office bleaching with either 60 seconds of ozone or 20 minutes of 38% H2O2. Notwithstanding, tooth sensitivity was significantly increased following bleaching with H2O2 in comparison to ozone. Ozone obviously does reduce the regularly clinically observed inconveniences of bleaching by means of H2O2; thus, ozone would seem worth considering for patients asking for in-office tooth bleaching. Keywords: esthetic dentistry, healOzone machine, hydrogen peroxide, ozone, tooth bleaching