Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease with no known cure. Maintaining quality of life (QOL) as the disease progresses is an important treatment goal. the purpose of this study is to identify factors that support QOL as ALS progresses. Changes in QOL were monitored in 162 individuals with ALS at 3- to 4-month intervals. Forty-nine of the participants survived in the study for over 1 year and were included in a longitudinal comparison. The 49 long-term participants were younger and stronger at Time 1 than were the participants who died before reaching the 1-year point. The McGill Quality of Life Scale demonstrated a high and stable QOL despite physical deterioration. Patients maintained a positive self-perception of their health despite the physical deterioration. Over time, self-perception of health and religiosity were shown to be significantly correlated with QOL. Results support the need for better instrumentation to enable future studies to more precisely measure multiple dimensions of ALS-related QOL, to identify reference points for self-ratings of both health and QOL, and to capture the religious and spiritual mechanisms related to QOL as individuals face the end of life.