Background: Multiple sclerosis (MS) is one of the world’s most common neurologic disorders and the leading cause of neurologic disability in young adults. This study aimed to investigate skill-based sexual enhancement counseling on Quality of Life (QLI) of women with Multiple Sclerosis.Methods: the present study is a quasi-experimental design with two groups. Forty-two patients with multiple sclerosis and their spouses (N=88) voluntarily participated in this study based on the inclusion and exclusion criteria. After obtaining the written consent forms, the couples were randomly assigned in two groups. The subjects in the intervention group (N=22 couples) received the skill-based sexual enhancement counseling program in six sessions (each for 90 minutes). The control group just received routine medical procedure during this period. Both groups completed three stages of pretest-posttest, and the standard MSQOL54 questionnaire 3 months later. Data were analyzed by SPSS-20 using descriptive and inferential statistics (repeated measures ANOVA, chi-square, Friedman and t-test).Results: The results showed that the participants' overall quality of life in the intervention group in pretest was 55.32±9.140 which increased to 73.89± 13.39 in posttest and to 92.59±20.45, 3 months later. Also, the physical quality of life showed a significant difference between the two groups 3 months after the intervention (P <0.05). There was a significant difference between the two groups in psychological quality of life, too. The subscales of physical and mental QLI such as sexual satisfaction, sexual function, emotional wellbeing, social function and energy in post-test and follow-up were significantly different (P<0.05).Conclusions: According to the findings, skill-based sexual enhancement counseling program is effective in quality of life enhancement. Therefore, it is recommended to health care providers to use enhancement program alongside the other rehabilitation and medical services to improve the patients' quality of life.