Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.