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The actual preventive and therapeutic effects of alkalinizing urine on melamine-induced bladder stones (cystolith) are not completely known. Using an ideal model, two experiments were conducted in Balb/c mice. The mice were fed a normal diet in controls and a melamine diet in the other groups. The first day was set as experiment-day 1. In "Experiment 1", either low-/mid-/high-dose sodium bicarbonate (SB) or sterile water was administered by intragastric perfusion (once daily) to the mice for 14 days. Relative to the model group, the mean pH of the urine in the SB groups was significantly elevated at 3 h after SB administration, with a significant decrease in cystolith incidence on experiment-day 14. In "Experiment 2", on experiment-day 12, the melamine diet was replaced by a normal diet in 4 groups with melamine withdrawal (MW). Meanwhile, either mid-/high-dose SB or sterile water was administered by intragastric perfusion (once) to the mice in the corresponding groups. On experiment-day 12, after an additional 8 h, the cystolith incidence was significantly reduced in the high-SB, MW + mid-SB and MW + high-SB groups than in the model group. In conclusion, low urinary pH is one of the main determinants of the formation of melamine-associated stones, urinary alkalinization can be achieved by a proper dose of oral SB, and SB acts to prevent and treat melamine-induced cystoliths in mice.