Introduction: Cardiopulmonary resuscitation (CPR) in microgravity requires specific methods to counteract weightlessness. Automatic chest com- pression devices (ACCDs) could improve CPR in microgravity. We aimed to compare ACCDs versus manual CPR in microgravity simulated through parabolic flights. Methods: This prospective, open, controlled study compared 3 ACCDs (LUCAS 3©, AUTOPULSE©, EASYPULSE©) to manual CPR during the 66th CNES (Centre National d’Etudes Spatiales) parabolic flights campaign onboard the Novespace Air Zero-G A310 aircraft. Chest compression depths and rates were monitored by a Laerdal© Resusci-Ann-QCPR manikin. Results: The LUCAS 3© device had a median compression depth of 53.0 [53.0–54.0] mm, significantly higher than the EASYPULSE©, AUTOPULSE©, and Manual CPR (Handstand method), measured at 29.0 [26.0–32.0] mm, 29.0 [27.5–30.7] mm and 34.5 [29.6–43.3] mm, respectively (p value < 0.001). Compression rates were 101 [101–101], 100 [100–100] and 80 [80–80] compressions per minute (cpm) for the LUCAS 3©, EASY- PULSE©, and AUTOPULSE©, respectively. Manual CPR provided a significantly higher compression rate with 115 [109–123] cpm (p value < 0.001). Conclusion: Only LUCAS 3© provided effective CPR according to international guidelines. ACCDs should implement microgravity CPR algorithms.