Clinically isolated syndrome (CIS) is an early sign of multiple sclerosis (MS). Despite being difficult to diagnose, the presentation of CIS is often accompanied by immunotherapy that is expensive and may have side effects. The purpose of this study was to evaluate CIS patients prescribed low dose naltrexone (LDN), an inexpensive, safe and tolerable compound that triggers endogenous enkephalin/endorphin release by the patient. LDN was prescribed to four female patients diagnosed with CIS in addition to FDA approved therapy. Retrospective chart reviews beginning in 2011 until present document that these women did not transition to clinically definite MS over a period of 4 years. Moreover, the patients reported that LDN therapy was without side effect and stabilized or improved their perceived quality of life and clinical status, including the reduction of fatigue. Thus, LDN may provide a safe and inexpensive alternative or addition to standard therapy of CIS.