Individuals fluent in sign language who have at least one deaf parent are considered native signers while those with non-signing, hearing parents are non-native signers. Musculoskeletal pain from repetitive motion is more common from non-natives than natives. The goal of this study was twofold: 1) to examine differences in upper extremity (UE) biomechanical measures between natives and non-natives and 2) upon creating a composite measure of injury-risk unique to signers, to compare differences in scores between natives and non-natives. Non-natives were hypothesized to have less favorable biomechanical measures and composite injury-risk scores compared to natives. Dynamometry was used for measurement of strength, electromyography for ‘micro’ rest breaks and muscle tension, optical motion capture for ballistic signing, non-neutral joint angle and work envelope, a numeric pain rating scale for pain, and the modified Strain Index (SI) as a composite measure of injury-risk. There were no differences in UE strength (all p≥0.22). Natives had more rest (natives 76.38%; non-natives 26.86%; p=0.002) and less muscle tension (natives 11.53%; non-natives 48.60%; p=0.008) for non-dominant upper trapezius across the first minute of the trial. For ballistic signing, no differences were found in resultant linear segment acceleration when producing the sign for ‘again’ (natives 27.59m/s2; non-natives 21.91m/s2; p=0.20). For non-neutral joint angle, natives had more wrist flexion-extension motion when producing the sign for ‘principal’ (natives 54.93°; non-natives 46.23°; p=0.04). Work envelope demonstrated the greatest significance when determining injury-risk. Natives had a marginally greater work envelope along the z-axis (inferior-superior) across the first minute of the trial (natives 35.80cm; non-natives 30.84cm; p=0.051). Natives (30%) presented with a lower pain prevalence than non-natives (40%); however, there was no significant difference in the modified SI scores (natives 4.70 points; non-natives 3.06 points; p=0.144) and no association between presence of pain with the modified SI score (r=0.087; p=0.680). This work offers a comprehensive analysis of all the previously identified UE biomechanics unique to signers and helped to inform a composite measure of injury-risk. Use of the modified SI demonstrates promise, although its lack of association with pain does confirm that injury-risk encompasses other variables in addition to a signer’s biomechanics.