BACKGROUND: Proper design of resistance training (RT) variables is a key factor to reach the maximum potential of neuromuscular adaptations. Among those variables, the use of RT performed to failure (RTF) may lead to a different magnitude of acute fatigue compared with RT not performed to failure (RTNF). The fatigue response could interfere with acute adaptive changes, in turn regulating long-term adaptations. Considering that the level of fatigue affects long-term adaptations, it is important to determine how fatigue is affected by RTF versus RTNF. OBJECTIVE: The aim of this systematic review and meta-analysis was to compare the effects of RTF versus RTNF on acute fatigue. METHODS: The search was conducted in January 2021 in seven databases. Only studies with a crossover design that investigated the acute biomechanical properties (vertical jump height, velocity of movement, power output, or isometric strength), metabolic response (lactate or ammonia concentration), muscle damage (creatine kinase activity), and rating of perceived exertion (RPE) were selected. The data (mean ± standard deviation and sample size) were extracted from the included studies and were either converted into the standardized mean difference (SMD) or maintained in the raw mean difference (RMD) when the studies reported the results in the same scale. Random-effects meta-analyses were performed. RESULTS: Twenty studies were included in the systematic review and 12 were included in the meta-analysis. The main meta-analyses indicated greater decrease of biomechanical properties for RTF compared with RTNF (SMD - 0.96, 95% confidence interval [CI] - 1.43 to - 0.49, p < 0.001). Furthermore, there was a larger increase in metabolic response (RMD 4.48 mmol·L-1, 95% CI 3.19-5.78, p < 0.001), muscle damage (SMD 0.76, 95% CI 0.31-1.21, p = 0.001), and RPE (SMD 1.93, 95% CI 0.87-3.00, p < 0.001) for RTF compared with RTNF. Further exploratory subgroup analyses showed that training status (p = 0.92), timepoint (p = 0.89), load (p = 0.10), and volume (p = 0.12) did not affect biomechanical properties; however, greater loss in the movement velocity test occurred on upper limbs compared with lower limbs (p < 0.001). Blood ammonia concentration was greater after RTF than RTNF (RMD 44.66 µmol·L-1, 95% CI 32.27-57.05, p < 0.001), as was 48 h post-exercise blood creatine kinase activity (SMD 0.86, 95% CI 0.33-1.42, p = 0.002). Furthermore, although there was considerable heterogeneity in the overall analysis (I2 = 83.72%; p < 0.01), a significant difference in RPE after RTF compared with RTNF was only found for studies that did not equalize training volumes. CONCLUSIONS: In summary, RTF compared with RTNF led to a greater decrease in biomechanical properties and a simultaneous increase in metabolic response, higher muscle damage, and RPE. The exploratory analyses suggested a greater impairment in the velocity of movement test for the upper limbs, more pronounced muscle damage 48 h post-exercise, and a greater RPE in studies with non-equalized volume after the RTF session compared with RTNF. Therefore, it can be concluded that RTF leads to greater acute fatigue compared with RTNF. The higher acute fatigue after RTF can also have an important impact on chronic adaptive processes following RT; however, the greater acute fatigue following RTF can extend the time needed for recovery, which should be considered when RTF is used. PROTOCOL REGISTRATION: The original protocol was prospectively registered (CRD42020192336) in the International Prospective Register of Systematic Reviews (PROSPERO).