BACKGROUND: Patients with Amyotrophic Lateral Sclerosis (ALS) undergo respiratory quarterly months controls to check respiratory muscle function, strenght and gas exchange. Arterial blood gas analysis is the gold standard for gas exchange follow-up, however it is an invasive test. End-tidal CO2 (EtCO2) is a non-invasive available tests to check the CO2 blood partial pressure.AIM: The present study aimed to correlate the reliability of ETCO2 vs PaCo2  in ALS patients undergoing routine out-patient controls.METHODS: Over six months period between June 2022 and January 2023, all consecutive ALS patients referring to the outpatients clinic for quarterly follow-up were enrolled and after written consent collection they undergo ETCO2 and PaCo2 tests before functional and muscular strength tests. Results were collected.RESULTS Sixty-6 patients were enrolled M/F (38/28), Bulbar/Spinal (6/60), Mean age (63±12). Twenty-3 out of 66 (25%) patients where already on noninvasive ventilation (NIV), the remaining never ventilated. Mean Vital Capacity was 65±13, mean peak cough flow 205±93, mean Snip 47±23 l/min. The comparison between Etco2 (33,13±5) vs mean  PaCo2 (37,3±5) showed aa statistically significance P <0.001 and good linear correlation (r= 0.55).CONCLUTIONS This study demonstrated in patients with ALS a good positive linear correlation between ETCO2 and PaCo2. Therefore, Etco2 demonstrated to be a reliable non-invasive test to check CO2 blood partial pressure during quaternary months follow-up.