Background: Non-ablative fractional laser is an effective modality for the treatment of periorbital wrinkling, one of the earliest signs of skin aging. Thermo-mechanical fractional injury (TMFI) therapy (Tixel®, Novoxel®, Israel) is an innovative technology that is now being used for facial skin rejuvenation. Our study compares the clinical results, side effects, and downtime profile between TMFI treatment and non-ablative fractional 1565 nm laser (ResurFX®, Lumenis, Israel). METHODS: This was a prospective study of 68 patients (64 women, 4 men) with skin types I–VI in two medical centers (34 from Israel, 34 from the USA) that were randomized to receive either TMFI or NAFL treatment for periorbital wrinkling. Patients received 3–5 treatments, 3–5 weeks apart. Six months after the last treatment, the change in Fitzpatrick Wrinkling Classification System (FWCS) was calculated by three non-involved physicians and compared to pretreatment results. Side effects and downtime profiles were assessed in each group (including VAS pain assessment, time required to refrain from work and social activity, and time required for the resolution of redness, edema, and crusts.). RESULTS: A moderate improvement in periorbital wrinkling was demonstrated in both groups, with an average improvement of 1.6 ± 0.6 in FWCS in the TMFI group and an average improvement of 1.7 ± 0.8 in the NAFL group (p < 0.001). Postprocedural VAS score was 5.86 ± 2.3 in the NAFL group and 4.01 ± 2.6 in the Tixel® group. Approximately 80% of subjects returned to both work and social activities two days postprocedure. Crusts were reported by 52% of patients in the TMFI group, compared to 16% of patients in the NAFL group more than 48 hours postprocedure (p < 0.05). There were no statistically significant differences in the other parameters between the two groups. CONCLUSION: TMFI is an effective and safe modality for the treatment of periorbital wrinkling, with comparable results to the 1565 nm NAFL.