We aimed to perform a prospective long-term follow-up of health-related quality of life (QOL) in ALS and to investigate the relationship of personality factors with changes in QOL and disease progression. Data on QOL were collected prospectively for 12 months from 31 ALS patients. Personality factors were studied using the NEO-FFI (NEO Five Factor Inventory). Monthly self-ratings of global QOL, and seven health-related QOL functions, as well as ALSFRS (ALS Functional Rating Scale) scores were analyzed using a linear mixed model approach. QOL and ALSFRS scores decreased during follow-up. Patients who scored higher on the agreeableness personality dimension, despite similar total duration of disease, had higher QOL at the beginning of the follow-up period but the reduction of QOL over time was significantly steeper than in patients who scored lower on agreeableness, associated with faster disease progression. These findings suggest that being less agreeable might serve as a protective factor with respect to QOL and disease progression in ALS.