From 1997 to 2003 we prospectively followed a cohort of ALS/MND patients. Patients were allocated to predetermined clinical phenotypes using the principles established in the modified El Escorial criteria. The date and region of symptom onset were carefully determined and their progression was scored using the Appel ALS rating scale. The four distinct clinical phenotypes: Global, Flail Arm, Flail Leg and Primary Lateral Sclerosis (PLS) demonstrated significantly different rates of progression and survival times. The Global ALS/MND phenotype can present with initial symptoms in any region and rapidly progresses to involve all segments, with symptoms due to a mixture of combined corticospinal tract and anterior horn cell dysfunction. The Global phenotype has the shortest survival and most rapid rate of disease progression. There was a significant difference in survival between Global bulbar onset and cervical onset disease but no significant difference in the rate of disease progression between the three Global subgroups as determined by the Appel/ALS rating scale. Flail patients had much slower rates of progression and significantly longer survival compared to the Global phenotype. Patients with Primary Lateral Sclerosis as expected progressed the slowest and survived the longest compared to the other clinical phenotypes. The utility of developing a method of assigning clinical phenotypes with similar survival and disease progression rates is discussed in relation to therapeutic trial design, practice benchmarking and clinico-pathological correlations.