BACKGROUND: Because systemic treatment of psoriasis is associated with several adverse effects, methotrexate (MTX), either topically or as targeted delivery, has become a more-interesting alternative. MATERIAL/METHODS: Methotrexate liposomes (LMTX) were prepared from DPPC, soy PC, egg yolk PC, and cholesterol. We studied the characterization, formulation of hydrogel (MTX 0.25%), and skin permeability, and compared LMTX gel with plain MTX gel and placebo for treating localized psoriasis in a double-blind study using albino mice. Gel formulations were applied daily, followed by irradiation with 80 joules from a 650-nm diode laser 3 times weekly for 12 weeks. Changes in disease signs and histopathological features were assessed. RESULTS: Drug release increased as laser energy increased following Higuchi's diffusion model and changed to zero order with energies > or = 80 J; significantly more MTX was released at all time intervals. Both LMTX and FMTX gels showed zero order kinetic release and antipsoriatic activity. During 8 months' follow-up, up to 60% of the patients treated with LMTX gel had no recurrence; this difference was statistically significant. No clinically significant changes were seen regarding blood or other laboratory variables. CONCLUSIONS: Application of an 80-J diode laser to 0.25% LMTX hydrogel was beneficial for relieving psoriasis and did not exert systemic toxicity.