The molecular weight of methotrexate (MTX) makes cutaneous penetration difficult. Oxygen flow could enhance the skin permeation of MTX diluted in the proprietary LP3 carrier system. This pilot study aims to assess the efficacy, safety, and tolerance of oxygen flow-assisted LP3-MTX3% for treating superficial skin cancers. Patients with superficial basal cell carcinoma (n = 12), extramammary Paget disease (n = 5), classic mycosis fungoides (MF; n = 10), and folliculotropic MF (n = 6) were included in the study and were treated with four weekly applications of oxygen flow-assisted LP3-MTX3%. Photographs and biopsies were performed before and one month after treatment. At one month after treatment, the mean superficial basal cell carcinoma erythema-crusting-thickness clinical score, the extramammary Paget disease erythema-oozing-scaling/hyperkeratosis-pain/pruritus clinical score, and the modified composite assessment of index lesion severity classic MF and folliculotropic MF scores were improved by 77.5% ± 17.1% (P < 0.0001), 66.7% ± 22.9% (P = 0.011), 51.3% ± 32.2% (P = 0.0007), and 27.8% ± 32.0% (P = 0.086), respectively. At one month after treatment, histology revealed partial and total clearances for superficial basal cell carcinoma (1/12, 11/12), extramammary Paget disease (4/5, 1/5), classic MF (8/10, 2/10), and folliculotropic MF (6/6, 0/6). Tolerance was excellent and no pain was observed. MTX was never detectable in serum at baseline and 1, 2, 3, 8, 24, 48, and 72 hours post-treatment. In conclusion, the interesting therapeutic efficacy of oxygen flow-assisted LP3-MTX3% for treating superficial basal cell carcinoma, extramammary Paget disease, and MF lesions prompts further studies on a larger scale.