Objectives Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease, restricts patients’ communication capacity a few years after onset. Promising proof-of-concept of Brain-Computer Interface (BCI) has already been demonstrated in ALS and locked-in patients, mostly in pre-clinical studies or only on few patients, but performance was estimated not yet high enough to support adoption by people with physical limitation of speech. Here, a visual BCI device is evaluated in a clinical study to test if disabled patients with multiple deficiencies related to ALS would be able to use BCI to communicate in a daily environment. Methods After clinical evaluation of physical, cognitive and language capacities, 20 patients with ALS were included. The BCI P300 speller system consisted of an EEG acquisition connected to real-time processing software, and separate keyboard display control software. It was equipped with original features such as optimal stopping of flashes and word prediction. The study consisted of two 3-block sessions (copy spelling, free spelling and free use) using the system in several modes of operation in view of evaluating its usability through its effectiveness, efficiency and satisfaction. Results Effectiveness is evidenced as 100% of participants successfully achieved all spelling tasks. Efficiency is supported considering over 95% of correct symbols were selected by 65% of participants. The average number of correct symbols/min ranged from 3.6 (without word prediction) to 5.04 (with word prediction). Participants expressed satisfaction with an average score of 8.7/10 on a Visual Analog Scale assessing comfort, ease of use and utility. Patients quickly learned how to operate this system which did not require much learning effort. Conclusion Word prediction and optimal stopping of flashes improve information transfer rate and make BCI competitive with alternative communication systems such as eye trackers. Remaining requirements to improve the device for a suitable ergonomic use are currently in progress.