To determine prevalence of musculoskeletal complaints (MSCs) in adults with major congenital upper limb differences (CoULD) compared to able-bodied controls, and to examine associations of MSCs and disability with various biopsychosocial factors. Questionnaire-based cross-sectional study assessing MSCs, disability (using the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH)), general and mental health status, physical work demands, and upper extremity range of motion. Seventy-one individuals with CoULD (participation rate: 41%) and 71 controls matched on age, gender, and education were included (49% female, mean age 28.9 years). Year prevalence of MSCs was significantly higher in the CoULD group (35%) than in the control group (18%). The CoULD group was less often employed and had lower scores on all measures of upper limb range of motion and hand grip. MSCs were associated with higher DASH scores and higher reported work demands. Disability was associated with female gender, more joints with limited range of motion, unemployment, and lower general and mental health. Factors associated with disability did not differ between groups. MSCs are a frequent problem in young adults with major CoULD. To prevent or reduce MSC and disability, clinicians and researchers should be aware of the associated factors. Implications for rehabilitation The year prevalence of musculoskeletal complaints (MSCs) in those with major congenital upper limb differences (CoULD) was approximately double to that of the control group, implying a potential relationship between CoULD and MSCs. Rehabilitation professionals should develop personalized strategies to manage work demands in those with CoULD, considering the association between MSCs and higher reported work demands. Recognizing the impact of a negatively perceived body image on mental health, clinicians should integrate psychological counseling into rehabilitation treatments to support mental well-being and improve overall quality of life in those with CoULD. ...