Combustion of cigarettes produces carbon monoxide (CO), which reduces oxygen-carrying capacity of the blood. The impact of CO level on the prognosis of patients with acute cardiac events is unknown. We hypothesized that elevated CO level is associated with impaired prognosis in patients hospitalized for acute cardiac events. From 7 to 22 April 2021, CO level was systematically measured in a prospective study including all consecutive patients admitted to intensive cardiac care unit in 39 centres throughout France. CO measurement was performed within 2 hours following admission using a standardized exhaled CO measurement device. The primary clinical outcome was in-hospital Major Adverse cardiac Events (MAE) defined by death, resuscitated cardiac arrest or cardiogenic shock. Among 1,387 consecutive patients screened (63.6 ± 14.8 years, 69.8% male), 33% were non smokers, 40% were former smokers and 27% were active smokers. CO level was similar in non smokers and former smokers (Mean ± SD 3.6 ± 3.6–3.3 ± 2.8, p = 0.12) and significantly increased in active smokers: 9.9 ± 6.4 ppm, p < 0.001). During hospitalisation, there were 58 (4.2%) in-hospital MAE. CO level was significantly associated with MAE in active smokers (OR [95%CI]: 1.14 [1.08–1.20] per unit ppm). The best threshold was >13 ppm defined by ROC curve analysis. CO level >13 ppm was significantly associated with MAE according to 3 models (model 1: age, sex, comorbidities, the main admission diagnosis: OR [95%CI]: 23.0 [8.1–78.3]– model 2: age, sex, the main admission diagnosis, systolic blood pressure, Killip class, and heart rate): 19.7 [6.9–65.1]– model 3: age, sex, the main admission diagnosis, BMI, previous COPD or asthma, oxygen flow rate – oxygen saturation – hemoglobin level at admission, and IV diuretic treatment): 37.8 [11.4–167]. Similar results were found using propensity score matching 2:1. In smokers with CO level ≤ 13 ppm, MAE rate was similar to non or former smokers (p = 0.65) (Fig. 1). In this prospective multicentre cohort of patients hospitalized for acute cardiac events, in hospital MAE are significantly and independently associated with CO level >13 ppm in smokers.