ABSTRACT Background and objectiveNon‐invasive ventilation (NIV) improves survival, quality of life and sleep in patients with amyotrophic lateral sclerosis (ALS). Nevertheless, NIV titration is conducted in different ways. We aim to provide more insight into NIV titration by comparing the effects of a spontaneous (S) and spontaneous‐timed (ST) modes on gas exchange, sleep architecture and patient‐ventilator asynchronies (PVAs).MethodsAfter an initial night of NIV titration, patients were randomized to S or ST mode in a cross‐over design. NIV was titrated using polysomnography, oximetry (oxygen saturation, SpO2 %) and transcutaneous carbon dioxide (PtcCO2 ) measurement. PVAs were analysed breath‐by‐breath.ResultsThirteen patients were analysed after inclusion. ST mode showed better results in gas exchange (minimal SpO2 %: 83 (80–89)% vs 87 (84–89)%; oxygen desaturation index: 15 (5–28)/h sleep vs 7 (3–9)/h sleep; PtcCO2 >55 mm Hg: 20 (0–59)% vs 0 (0–27)% total sleep time for S and ST mode, respectively, all P < 0.05) and respiratory events (obstructive: 8.9 (1.2–18.3)/h sleep vs 1.8 (0.3–4.9)/h sleep and central: 2.6 (0.4–14.1)/h sleep vs 0.2 (0.0–1.1)/h sleep for S and ST mode, respectively, both P < 0.01). No differences in sleep architecture were found. Ineffective efforts and respiratory events were more frequently present in S mode.Nevertheless, four patients were discharged on S mode as these patients showed clinically better results for sleep architecture and PVA during the night on S mode.Conclusion ST mode shows better results in gas exchange, respiratory events and PVA. Nevertheless, accurate NIV titration remains necessary as some patients show equal or better results when using the S mode.