The possible use of regenerated silk fibroin gels as in situ film forming formulations for cutaneous administration of drugs was studied. Ethanol was selected as volatile and skin tolerant solvent to favor the sol-gel transition of silk fibroin solutions. Glycerin was chosen to ameliorate the gel texture profile. Eighteen placebo formulations were prepared to individuate the optimal component ratios as a function of the texture analysis, spreadability and drying time. The in vitro biopharmaceutical performance was investigated by in vitro permeation test through human epidermis on formulations loading caffeine as a model drug. The data evidenced that the optimal technological performances were achieved using gels containing 70% ethanol and silk fibroin/glycerin ratio from 0.18 to 0.36. The caffeine flux (J) through the skin was significantly improved due to an increase of the drug thermodynamic activity (hydro-alcoholic solution: J ˜ 0.8 μg/cm2/h; in situ formed film: J ˜ 1.4–1.7 μg/cm2/h). In conclusion, silk fibroin can be advantageously proposed as a novel film forming material to develop dosage forms to be topically applied.