Background: Although several plants and procedures for treatment of kidney stone disease in Iranian folk medicine, Urolithiasis has been an important problem for patients, yet. Objective: Aim of present study, was the investigation of effect of Cucumis melo fruit skin hydro-alcoholic extract on calcium oxalate crystallization was studied in vitro. Methods: At first, hydro-alcoholic extract of plant at doses of 0.25, 0.5, 1, 2 and 4 mg/ml were prepared. Urine samples were collected from 6 individual men without kidney stone history. The urine samples were centrifuged. Calcium oxalate crystallization was induced by adding sodium oxalate to urine samples. Then, number and size of calcium oxalate crystals were measured by spectrophotometer and calibration of ocular lens of light microscope in control (without plant extract) and experimental (in presence of different of doses plant extract) groups, respectively. Results: Different doses of hydro-alcoholic extract of plant increased percent of small crystals (2.5-5 and 6-9 ?), while decreased percent of big crystals (17-21, 22-30 and 31-40 ? in comparison to control samples. On the other hand, the plant increased mono-hydrate calcium oxalate crystals in comparison to di-hydrate calcium oxalate crystals. Also, the extract increased number of calcium oxalate crystals. Conclusion: Present results showed that hydro-alcoholic extract of Cucumis melo fruit skin could facilitate kidney stones excretion by decreasing size of crystals. So, it could prevent formation of kidney stone primary nucleus.