Objective: This study examined the relationship between medication gaps and severe MS relapses. Methods: Subjects were selected from the PHARMetrics database if they had at least one MS drug (Avonex®, Betaseron®, Copaxone®, Rebif®) claim from January 1, 2000 through December 31, 2004, and, were continuously eligible for 24-months following their first disease modifying prescription (index date), in addition to 6-months prior to the index date. Subjects were excluded if the were <18 or >65 years of age, exposed to Tysabri® after the index date, had evidence of study medication use in a healthcare facility, or lived in a long-term care facility. A severe MS relapse was defined as an “MS-related” hospitalization or emergency room visit. Maximum gap in therapy (Maxgap), was defined as the longest continuous period with no evidence of study medication availability (based on dispensing date and days supply). Maxgap was categorized as 0–10 days, 11–89 days, and 90+ days. Covariates included, age, gender, region, and treatment status (new or existing), comorbidities, and therapy type (mono- or multi-drug therapy). Results: Subjects (N=2388) had a mean age of 43.9 years, 76.7% were new patients, 8.1% had at least 1 severe MS relapse over the 24-month study period, and 76.4% were female. Maxgap had a significant odds ratio (OR) of 1.925 (p=0.007) for the 90+ day group (0–10 day reference). Monotherapy use for the 4 study drugs was associated with reduced risk of severe relapse (ORs between 0.450 and 0.552). Other significant covariates were comorbidity and East region (ORs=1.090 and 1.495 respectively). Age, gender, and the other regions were not significant at alpha = 0.05. Conclusion: Gaps in MS drug therapy longer than 90 days are associated with a higher risk of severe MS relapse compared to short or no gaps in treatment.