Non-invasive positive pressure ventilation (NPPV) can improve survival in ALS patients with advanced respiratory impairment, but it is not known if it is beneficial earlier in the disease course. A retrospective cohort study of patients with ALS was performed comparing survival from time of diagnosis in subjects who started NPPV use when their FVC was >or=65% predicted (Early NPPV) with subjects who started NPPV when their FVC was below 65% predicted (Standard NPPV). The Early group (n = 25) and the Standard group (n = 67) were similar except for pulmonary function (mean FVC in Early NPPV group = 74.3+/-10.1% predicted and 48.3+/-11.3 in Standard group, p<0.001). The median time from ALS diagnosis to death was significantly longer in the Early NPPV group (2.7 years vs. 1.8 years, p = 0.045). This remained significant after adjustment for potential confounding factors (H.R. = 0.55, 95% CI 0.31-0.98). Survival from time of diagnosis was nearly one year longer in the Early group. Until more definitive data are available from randomized trials, our findings suggest that clinicians either encourage earlier use of NPPV or use more sensitive tests for respiratory muscle impairment than upright FVC.