Objective: Mindfulness is the process of actively making new distinctions, rather than relying on habitual or automatic categorisations from the past. Mindfulness has been positively associated with physical well-being, better recovery rates from disease or infections, pain reduction and overall quality of life (QOL). Amyotrophic lateral sclerosis (ALS) is a rare, progressive and fatal neurodegenerative disease, clinically characterised by progressively increasing weakness leading to death, usually within five years. There is presently no cure for ALS, and it is considered one of the most genetically and biologically driven illnesses. Thus far, the aims of psychological studies on ALS have focused on understanding patient - and, to a lesser extent, caregiver - QOL and psychological well-being. No previous study has investigated the influence of psychological factors on ALS. Methods: A sample of 197 subjects with ALS were recruited and assessed online twice, with a duration of four months between the two assessments. Assessments included measurements of trait mindfulness, physical impairment, QOL, anxiety and depression. The influence of mindfulness as predictor of changes in physical impairments was evaluated with a mixed-effects model. Results: Mindfulness positively influenced the change of physical symptoms. Subjects with higher mindfulness experienced a slower progression of the disease after four months. Moreover, mindfulness at first assessment predicted higher QOL and psychological well-being. Conclusions: The available data indicate that a psychological construct - mindfulness - can attenuate the progress of a disease that is believed to be almost solely biologically driven. The potential implications of these results extend well beyond ALS.