Oral isotretinoin is successfully used for the treatment of moderate and severe acne vulgaris and prevention of acne scars and its psychosocial sequels. Acne flare as an adverse event of this agent, which is characterized by an initial exacerbation of acne, develops worsening lesions and increases the risk of scar development. For the first time, the efficacy of carboxytherapy was assessed in the management of acne flare in patients with moderate to severe acne vulgaris under isotretinoin therapy. This study is a case series of 10 subjects with moderate to severe facial acne. Along with initiation of isotretinoin, carboxytherapy was randomly performed on one side of the face. The response to treatment was studied through evaluation of the number of inflammatory and non-inflammatory acne lesions, modified total lesion count (mTLC), modified acne severity index (mASI), subjective satisfaction, and scar correction. The minimum age of the subjects was 24.4 years. The male to female ratio was 2:8. The effect of carboxytherapy on decrease of papule counts and mASI (as important index of acne flare) and increase of subjective satisfaction was statistically significant. In comparison with the control group, the effect of carboxytherapy on white and black comedone, pustule, and cyst counts, and mTLC was better in the interventional group, their differences were not statistically significant. In addition to overcoming acne flare, carboxytherapy could decrease scar severity. No significant side effects were reported. Carboxytherapy can be considered as an effective and safe adjuvant therapy with oral isotretinoin to overcome acne flare and decrease risk of acne scarring.