Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system that is often associated with a myriad of physical and cognitive impairments. Sexual dysfunction (SD) is a common yet often overlooked symptom in MS. The present study aimed to explore one type of SD, namely perceived fear of sexual rejection among individuals with MS. Predictor variables, including gender, age, employment status, bladder/bowel symptoms, mental health status, and disease severity were explored. The sample comprised of 5,979 respondents to the spring 2006 North American Research Committee on Multiple Sclerosis Questionnaire. Respondents who answered the fear of sexual rejection item on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) in the MS Intimacy and Sexuality Section were included in the analysis. The Patient Determined Disease Steps was used to measure disease severity. The 12-Item Short-Form Health Survey, Version 2, Mental Health Scale was used to assess mental health. The MSISQ-19 was used to assess fear of sexual rejection. A logistic regression analysis was performed. The full model containing all predictors was statistically significant, χ2 (7, N = 5,979) = 1,426.01, p < 0.001, indicating that the model was able to distinguish between respondents who reported fear of sexual rejection and those who did not. The model as a whole explained between 21.2 and 29.0 % of the variance in fear of sexual rejection, and correctly classified 72.9 % of cases. The strongest predictor of reporting fear of sexual rejection was gender. Findings indicate that SD, particularly fear of sexual rejection, is a complex and multi-faceted phenomenon. This study highlights the need for interventions designed to help people with disabilities work through their fears and build their sexual confidence to help facilitate healthy sexual activity.