Upper limb exoskeletons are recommended to alleviate muscle fatigue, particularly in working conditions inducing musculoskeletal discomfort like overhead work. However, wearing an exoskeleton might introduce cognitive-motor interference, affecting performance. Understanding its neural impact and potential gender differences in design effects is crucial. Therefore, the aim of this study is to examine exoskeleton effects addressing cross-gender comparisons, and exploring the impact on cognitive and physical workload in real-world scenarios. The research questions address the impact of exoskeleton use on muscle synergies, upper body posture, cognitive resources, comfort/discomfort, acceptance and usability. The cross-sectional study integrates a multifactorial mixed-measure design. Participants are grouped by gender (female vs. male) and working condition (with vs. without exoskeleton). Motor performance and underlying neuronal correlates (fNIRS) will be analyzed. Based on an a priori sample size calculation, 80 participants (40 female/40 male) will be recruited. Working performance will be assessed by 1. Physical Performance Task (PILE task) and 2. Precision Task (following the Fitts paradigm), while body postures will be monitored with an Xsens motion capture system. Brain activation will be captured with an fNIRS system comprising 32 active optodes. Postural comfort/discomfort, acceptance, and usability will be reported via standardized questionnaires. The study will gain insights into potential gender differences in exoskeleton use and will contribute to designing and optimizing the implementation of exoskeletons by considering muscle synergies, movement variability and cognitive resource allocation. Additionally, the study also highlights user discomfort, a crucial factor that could impede widespread adoption, particularly among females, in real-world scenarios.