Background: Information on causes of death (CODs) for patients with multiple sclerosis (MS) in the United States is sparse and limited by standard categorizations of underlying and immediate CODs on death certificates. Prior research indicated that excess mortality among MS patients was largely due to greater mortality from infectious, cardiovascular, or pulmonary causes. Objective: To analyze disease categories in order to gain insight to pathways, which lead directly to death in MS patients. Methods: Commercially insured MS patients enrolled in the OptumInsight Research database between 1996 and 2009 were matched to non-MS comparators on age/residence at index year and sex. The cause most-directly leading to death from the death certificate, referred to as the "principal" COD, was determined using an algorithm to minimize the selection of either MS or cardiac/pulmonary arrest as the COD. Principal CODs were categorized into MS, cancer, cardiovascular, infectious, suicide, accidental, pulmonary, other, or unknown. Infectious, cardiovascular, and pulmonary CODs were further subcategorized. Results: 30,402 MS patients were matched to 89,818 controls, with mortality rates of 899 and 446 deaths/100,000 personyears, respectively. Excluding MS, differences in mortality rate between MS patients and non-MS comparators were largely attributable to infections, cardiovascular causes, and pulmonary problems. Of the 95 excessive deaths (per 100,000 personyears) related to infectious causes, 41 (43.2%) were due to pulmonary infections and 45 (47.4%) were attributed to sepsis. Of the 46 excessive deaths (per 100,000 person-years) related to pulmonary causes, 27 (58.7%) were due to aspiration. No single diagnostic entity predominated for the 60 excessive deaths (per 100,000 person-years) attributable to cardiac CODs. Conclusions: The principal COD algorithm improved on other methods of determining COD in MS patients from death certificates. A greater awareness of the common CODs in MS patients will allow physicians to anticipate potential problems and, thereby, improve the care that they provide. © 2014 Goodin et al.