Improving quality of life (QoL) is a major goal in ALS palliative care. Previous studies performed on the general ALS population showed no relationship between QoL and disease progression. ALS subjects participating in clinical trials may differ from those in the general ALS population. We explored the relationship between QoL and disease progression in 412 subjects enrolled in a minocycline trial. We examined correlations between Single Item McGill Quality of Life Scale (MQoL-SIS) score and disease duration, ALS Functional Rating Scale Revised (ALSFRS-R) score, FVC, and survival rate. We also analyzed how NIV and PEG affect QoL. Within subjects, MQoL-SIS scores correlated with ALSFRS-R and FVC (p<0.001). MQoL-SIS declined over time (p<0.001) and correlated with the decline of ALSFRS-R (p<0.001). MQoL-SIS tended to improve after initiation of NIV (p=0.07). There was a significant reduction in the rate of MQoL-SIS decline (p<0.001) after initiation of PEG. Subjects with slower QoL decline survived seven months longer than those with faster QoL decline (p<0.01). Our study demonstrated that QoL does decline with advancing ALS in subjects who participated in a minocycline trial, that the slope of QoL predicts survival, and that both NIV and PEG have beneficial impacts on QoL.