The study investigated the impact of sedation level variability (SLV) during the first 72 hours in the ICU in mechanically ventilated critically ill patients from the MIMIC-IV database (2008–2019). SLV was measured by the time coefficient of variation (KV) from the exponentially transformed RASS score, and patients were divided by median KV into low (n=1759) and high SLV (n=1749) groups, balanced by the stabilized inverse probability weighting method. The low SLV group had a higher risk of 28-day mortality [aHR 1.83 (95% CI 1.83), p < 0.001] and 90-day ICU mortality [aHR 1.51 (95% CI 1.32–1.71), p < 0.001]. The groups did not differ in prolonged mechanical ventilation on day 14 or days without ventilation on day 21 in the ICU. The negative effect of low SLV on mortality was evident only in patients with less than 60% of the time in the RASS target range, not in those with ≥ 60%. Patients with less than 60% of the time in the RASS target range are particularly susceptible to this negative effect.