Background: Acute and severe infections are an absolute indication for the use of intravenous broad-spectrum antibiotics. However, previous studies have found inconsistent clinical advantages of prolonged (extended [≥ 3-hour infusion] or continuous [24-hour fixed rate infusion]) over intermittent (6, or 8, or 12 interval hours infusion) infusion. The clinical superiority between prolonged and intermittent infusion in treating acute and severe infections thus continues to be elusive. We conducted a meta-analysis to summarize all published randomized controlled trials (RCTs), prospective and retrospective observational studies to determine whether prolonged infusion, compared to intermittent infusion, is correlated with lower mortality and better clinical outcome. Methods: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to August 31, 2018) and EMBASE (January 1, 1980 to August 31, 2018) with no restrictions to collect RCTs and observational studies comparing prolonged infusion with intermittent infusion of the same intravenous administered antibiotics among adult hospitalized patients. A total of 43 studies including 30 RCTs, 5 prospective observational studies and 8 retrospective observational studies were identified. Results: In comparison with intermittent infusion, prolonged infusion of antibiotics was associated with a reduction in all-cause mortality (pooled relative risk [RR] = 0. 77, 95% confidence interval [CI] = 0. 66– 0. 89) and improvement in clinical cure (RR = 1. 11, 95% CI = 1. 04– 1. 19), which was also observed in subgroups such as non-RCTs (mortality, RR = 0. 63, 95% CI = 0. 48– 0. 81; clinical cure RR = 1. 33, 95% CI = 1. 13– 1. 57) or studies with patients and APACHE II scores 15 (mortality, RR = 0. 74, 95% CI 0. 63– 0. 89; clinical cure RR = 1. 19, 95% CI = 1. 07– 1. 32). Moreover, in RCTs, mortality (RR = 0. 86, 95% CI 0. 72– 1. 03) between the two dosing strategies was not remarkably changed but clinical cure (RR = 1. 07, 95% CI = 1. 01– 1. 13) showed a significant advantage for prolonged infusion. Additionally, no significant differences in mortality between the two dosing strategies was found (RR = 0. 87, 95% CI = 0. 70– 1. 09) but a distinct improvement in clinical cure was observed (RR = 1. 14, 95% CI = 1. 02– 1. 28) in the prolonged infusion group for septic patients. Among two infusion modes, statistically significant severe adverse events were not reported (RR=0. 83, 95% CI = 0. 62– 1. 13). Conclusion: Better outcomes in hospitalized patients, especially in those who were critical ill, were reported in prolonged infusion of intravenous antibiotics compared with traditional intermittent infusion.