OBJECTIVES:  Disease-modifying therapies (DMTs) for multiple sclerosis (MS) have various monitoring requirements, depending upon the safety profile of the drug. There is, however, very limited research examining the extent to which MS patients adhere to these monitoring guidelines. METHODS:  Truven’s Commercial Claims and Encounters database (January 1, 2009–December 31, 2014) was analyzed. Individuals ≥18 years of age with an MS diagnosis who initiated treatment with a DMT (first such date = index date) and had continuous insurance coverage from 3 months prior through 15 months post-index date were included. There were 23,289 cases of drug initiation included in the analysis: 8453 glatiramer acetate, 7951 interferon beta-1a, 2943 natalizumab, 2150 fingolimod, 1746 dimethyl fumarate, 392 teriflunomide, and 14 alemtuzumab. Descriptive analyses were performed. RESULTS:  The majority did not completely adhere to monitoring guidelines. For example, liver function tests are recommended for fingolimod prior to initiation and for interferon beta-1a (3 or 4 times), teriflunomide (7 times), and alemtuzumab (13 times) during the year following initiation. Real-world adherence to this guideline ranged from 28.6% (alemtuzumab) to 64.7% (fingolimod). In the 1 year post-DMT initiation, only 41.5% of fingolimod patients had 2 ophthalmologist visits, 9.4% of natalizumab patients had JC virus antibody tests, and 56.2% of natalizumab patients received a brain magnetic resonance imaging as the Federal Drug Administration (FDA) label recommends. Furthermore, 0% for alemtuzumab patients were completely adherent to annual monitoring guidelines, which included 13 liver function tests, complete blood counts, serum creatinine and urinalysis tests, 5 thyroid function tests, and receipt of 5 doses of acyclovir. CONCLUSIONS:  The majority of MS patients were not completely adherent to DMT monitoring guidelines. Non-adherence may impact the risk:benefit balance of DMTs and suggest an advantage for glatiramer acetate, which is not associated with any FDA recommended laboratory monitoring.