Adenomyosis is a difficult disease to manage and currently there is no investigative drug for adenomyosis on the horizon. We have previously reported in a pilot study that valproic acid (VPA) appears to be effective in treating adenomyosis. In this case series, we further evaluated the efficacy of VPA, with or without a progestin-containing intrauterine device, in the treatment of patients with adenomyosis. We recruited 12 patients with confirmed adenomyosis who complained of dysmenorrehea and had enlarged uterus. All patients took VPA for 3 months, then randomly assigned to 2 groups, 1 receiving no further treatment and the other were inserted with a levonorgestrel-releasing intrauterine system (Mirena) and were followed up for an additional 3 months. The primary outcome measures were the severity of dysmenorrhea and uterine size. Both measures were evaluated prior to the drug treatment and 3 and 6 months after the drug treatment, respectively. We found that VPA treatment resulted in complete resolution of dysmenorrhea and an average reduction in uterine size by 26% 6 months after the treatment, regardless of whether Mirena was used or not. Moreover, the amount of menses decreased significantly. Thus, VPA appears to be well tolerated and a promising drug for treating adenomyosis.