Background There is a lack of research considering acute fatigue responses to high- and low-load resistance training as well as the comparison between male and female responses. Furthermore, limited studies have considered fatigue response testing with the inclusion of perceptions of discomfort and exertion. Methods The present study included males (n = 9; 23.8 ± 6.4 years; 176.7 ± 6.2 cm; 73.9 ± 9.3 kg) and females (n = 8; 21.3 ± 0.9 years; 170.5 ± 6.1 cm; 65.5 ± 10.8 kg) who were assessed for differences in fatigue (i.e., loss of torque at maximal voluntary contraction (MVC)) immediately following isolated lumbar extension (ILEX) exercise at heavy- (HL) and light-(LL) loads (80% and 50% MVC, respectively). Participants also reported perceptual measures of effort (RPE-E) and discomfort (RPE-D) between different resistance training protocols. Results Analysis of variance revealed significantly greater absolute and relative fatigue following LL compared to HL conditions (p < 0.001). Absolute fatigue significantly differed between males and females (p = 0.012), though relative fatigue was not significantly different (p = 0.160). However, effect sizes for absolute fatigue (HL; Males = ?1.84, Females = ?0.83; LL; Males = ?3.11, Females = ?2.39) and relative fatigue (HL; Males = ?2.17, Females = ?0.76; LL; Males = ?3.36, Females = ?3.08) were larger for males in both HL and LL conditions. RPE-E was maximal for all participants in both conditions, but RPE-D was significantly higher in LL compared to HL (p < 0.001) with no difference between males and females. Discussion Our data suggests that females do not incur the same degree of fatigue as males following similar exercise protocols, and indeed that females might be able to sustain longer exercise duration at the same relative loads. As such females should manipulate training variables accordingly, perhaps performing greater repetitions at a relative load, or using heavier relative loads than males. Furthermore, since lighter load exercise is often prescribed in rehabilitation settings (particularly for the lumbar extensors) it seems prudent to know that this might not be necessary to strengthen musculature and indeed might be contraindicated to avoid the increased fatigue and discomfort associated with LL exercise.