The present study aimed to compare the effects of repetition duration-, volume-, and load-matched resistance training to muscular failure (MMF) or not to muscular failure (NMF) on maximal voluntary isometric knee extensor strength. This design also allowed testing of the efficacy of "5×5" training. Nine recreationally active males (age, 21.4 ± 1.2 years; height, 1.79 ± 0.07 m; weight, 78.4 ± 7.1 kg) performed unilateral resistance training at 80% of maximal torque at 2×/week for 6 weeks. Using their nondominant leg, participants performed 5 sets of 5 repetitions (NMF). Using their dominant leg, participants performed 25 repetitions in as few sets as possible (MMF). All repetitions were performed at a pace of 2 s concentric, 1 s isometric pause, and 2 s eccentric with a 2-min rest interval between sets. Analyses identified significant pre- to post-intervention strength increases for both MMF and NMF, with effect sizes (ESs) of 2.01 and 1.65, respectively, with no significant differences between conditions (p > 0.05). Peak and mean ratings of perceived exertion (RPEs) were significantly higher for MMF compared with NMF conditions (p < 0.0001), and a tendency for significantly higher RPE values reported for later sets for the NMF condition. Total training time per session was significantly longer for NMF compared with MMF (p < 0.001). The present study suggests that in untrained participants, resistance training NMF produces equivocally the same strength increases as training to MMF when volume-matched. However, resistance training to MMF appears to be a more time-efficient protocol and may produce greater strength gains as indicated by a larger ES.