BACKGROUND Daily sedation interruption (DSI) is thought to limit drug bioaccumulation, promote a more awake state, and thereby reduce the duration of mechanical ventilation. Available evidence has shown DSI to either reduce, not alter, or prolong the duration of mechanical ventilation. OBJECTIVE The primary objective of this review was to compare the total duration of invasive mechanical ventilation for critically ill adult patients requiring intravenous sedation who were managed with DSI versus those with no DSI. Our other objectives were to determine whether DSI influenced mortality, intensive care unit (ICU) and hospital lengths of stay, adverse events, the total doses of sedative drug administered, and quality of life. METHODS We searched, from database inception to February 2014, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1); MEDLINE (OvidSP); EMBASE (OvidSP); CINAHL (EBSCOhost); Latin American and Caribbean Health Sciences Literature (LILACS); Web of Science Science Citation Index; Database of Abstracts of Reviews of Effects (DARE); the Health Technology Assessment Database (HTA Database); trial registration websites, and reference lists of relevant articles. We did not apply language restrictions. The reference lists of all retrieved articles were reviewed for additional, potentially relevant studies. METHODS We included randomized controlled trials that compared DSI with sedation strategies that did not include DSI in mechanically ventilated, critically ill adults. METHODS Two authors independently extracted data and three authors assessed risk of bias. We contacted study authors for additional information as required. We combined data in forest plots using random-effects modelling. A priori subgroups and sensitivity analyses were performed. RESULTS Nine trials were used in the analysis (n = 1282 patients). These trials were found to be predominantly at low risk of bias. We did not find strong evidence of an effect of DSI on the total duration of ventilation. Pooled data from nine trials demonstrated a 13% reduction in the geometric mean, with relatively wide confidence intervals (CI) indicating imprecision (95% CI 26% reduction to 2% increase, moderate quality evidence). Similarly, we did not find strong evidence of an effect on ICU length of stay (-10%, 95% CI -20% to 3%, n = 9 trials, moderate quality evidence) or hospital length of stay (-6%, 95% CI -18% to 8%, n = 8 trials, moderate quality evidence). Heterogeneity for these three outcomes was moderate and statistically significant. The risk ratio for ICU mortality was 0.96 (95% CI 0.77 to 1.21, n = 7 trials, moderate quality evidence), for rate of accidental endotracheal tube removal 1.07 (95% CI 0.55 to 2.12, n = 6 trials, moderate quality evidence), for catheter removal 1.48 (95% CI 0.76 to 2.90, n = 4 trials), and for incidence of new onset delirium 1.02 (95% CI 0.91 to 1.13, n = 3 trials, moderate quality evidence). Differences in the doses of any drug used or quality of life score (Short Form (SF)-36) did not reach statistical significance. Tracheostomy was performed less frequently in the DSI group (RR 0.73, 95% CI 0.57 to 0.92, n = 6 trials, moderate quality evidence). Sensitivity analysis of unlogged data resulted in similar findings. Post hoc analysis to further explain heterogeneity, based on study country of origin, showed that studies conducted in North America resulted in a reduction in the duration of mechanical ventilation (-21%, 95% CI -33% to -5%, n = 5 trials). CONCLUSIONS We have not found strong evidence that DSI alters the duration of mechanical ventilation, mortality, length of ICU or hospital stay, adverse event rates, drug consumption, or quality of life for critically ill adults receiving mechanical ventilation compared to sedation strategies that do not include DSI. We advise that caution should be applied when interpreting and applying the findings as the overall effect of treatment is always < 1 and the upper limit of the CI is only marginally higher than the no-effect line. These results should be considered unstable rather than negative for DSI given the statistical and clinical heterogeneity identified in the included trials.