Prior studies suggest that native (born to at least one deaf or signing parent) and non-native signers have different musculoskeletal health outcomes from signing, but the individual and combined biomechanical factors driving these differences are not fully understood. Such group differences in signing may be explained by the five biomechanical factors of American Sign Language that have been previously identified: ballistic signing, hand and wrist deviations, work envelope, muscle tension, and “micro” rests. Prior work used motion capture and surface electromyography to collect joint kinematics and muscle activations, respectively, from ten native and thirteen non-native signers as they signed for 7.5 min. Each factor was individually compared between groups. A factor analysis was used to determine the relative contributions of each biomechanical factor between signing groups. No significant differences were found between groups for ballistic signing, hand and wrist deviations, work envelope volume, excursions from recommended work envelope, muscle tension, or “micro” rests. Factor analysis revealed that “micro” rests had the strongest contribution for both groups, while hand and wrist deviations had the weakest contribution. Muscle tension and work envelope had stronger contributions for native compared to non-native signers, while ballistic signing had a stronger contribution for non-native compared to native signers. Using a factor analysis enabled discernment of relative contributions of biomechanical variables across native and non-native signers that could not be detected through isolated analysis of individual measures. Differences in the contributions of these factors may help explain the differences in signing across native and non-native signers.