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International Journal of Exercise Science 15(4): 782-796, 2022. This study examined changes in maximal voluntary isometric contraction (MVIC) force following dominant (Dm) and nondominant (NDm) unilateral, handgrip isometric holds to failure (HTF) for the exercised ipsilateral (IPS) and non-exercised contralateral (CON) limbs and determined if there are sex- and hand- (Dm vs NDm) dependent responses in the HTF time, performance fatigability (PF) for the exercised IPS limb, and changes in MVIC force for the CON limb after unilateral fatigue. Ten men and 10 women (Age = 22.2 years) completed an isometric HTF at 50% MVIC for the Dm and NDm hand on separate days. Prior to, and immediately after the HTF, an MVIC was performed on the IPS and CON limbs, in a randomized order. The Dm (130.3 ± 36.8 s) HTF (collapsed across sex) was significantly longer (p = 0.002) than the NDm (112.1 ± 34.3 s). The men (collapsed across hand) demonstrated IPS (%D = 22.9 ± 10.8%) PF and CON facilitation (%D = -6.1 ± 6.9%) following the HTF, while the women demonstrated differences in PF between the Dm and NDm hands for the IPS (%D Dm = 28.0 ± 9.4%; NDm = 32.3% ± 10.1%; p = 0.027), but not the CON limb (%D Dm = -1.6 ± 5.7%; NDm = 1.7 ± 5.9%). The cross-over facilitation of the CON limb for men, but not women, following a unilateral, isometric handgrip HTF may be related to post-activation potentiation.