BACKGROUND: The selective photothermolysis of sebaceous follicles with topically applied gold nanoparticles, followed by light exposure, shows good efficacy for acne treatment. Methods such as sonophoresis or CO fractional laser can help to deliver gold nanoparticles efficiently. Additionally, ethosomes are introduced to enhance the skin penetration of gold nanoparticles. AIMS: This study aimed to assess the effectiveness and safety of the combination of CO fractional laser and gold photothermal therapy for acne. PATINENTS/METHODS: Twenty-four patients with moderate to severe acne were involved. They were randomly divided into two groups: Group 1 received CO fractional laser treatment followed by ethosome gold nanoparticle ampule application, while Group 2 applied the ampule with sonophoresis. After ampule application, all patients underwent long-pulsed Nd:YAG laser treatment (1064 nm wavelength, fluence 4.5 J/cm, frequency 10 Hz, pulse duration 0.3 ms, and spot size 10 mm). Clinical evaluation, biopsy, and blood tests for gold detection assessed the effectiveness and safety of the treatments. RESULTS: Ethosome gold photothermal therapy demonstrated significant clinical and histological improvements in acne vulgaris among Asian patients, showing no serious adverse effects or systemic absorption of gold nanoparticles. CONCLUSIONS: Patients treated with CO fractional laser pretreatment before ampule application showed reductions across all acne lesion types, including comedones, and experienced improvement in acne scars.