We examined predictors of clinically significant levels of psychological distress among individuals with upper limb loss (ULL). A multisite, cross-sectional study completed at six prosthetic rehabilitation centres throughout the United States. Oral administration of a brief assessment battery to 307 participants with ULL including demographic variables, injury information, screening instruments for PTSD and depression, pain interference, and activity restriction measures. Hierarchical multinomial logit models were conducted. Outcome groups were created using recommended cut-off scores on brief screening measures of depression and PTSD. Final models were assessed including relative risk ratios and marginal effects. Over half of the sample screened positive for depression, PTSD, or both. Eight individuals exceeded the recommended cut-off score indicative of PTSD only (2.6%), and 106 participants (34.5%) screened positive for depression only. Moreover, 64 participants (20.8%) reported co-occurring PTSD and depression. Subsequent models revealed women and ethnic minority participants were more likely to have clinically significant levels of depression and PTSD. Greater restriction in activity and increased pain interference also predicted psychological distress. These findings indicate a significant number of individuals with ULL experience clinically significant levels of psychological distress, and routine clinical assessment of depression and PTSD is warranted. Women and individuals from ethnic minorities may be particularly at risk, regardless of the severity and cause of ULL. Restrictions in preferred and goal-directed activities and persistent pain are also contributing factors. Psychological interventions that address these issues are indicated. Statement of contribution What is already known on this subject? Research investigating psychological reactions and adjustment after limb loss has primarily focused on lower limb loss. Little research has investigated psychological adjustment or distress following upper extremity loss. Lower extremity limb loss is more likely to be from a disease process while upper extremity limb loss is more likely to be due to traumatic injuries. Upper extremity limb loss possesses a qualitatively different experience as upper limb amputation is more readily apparent to others, impacts activities of daily living, and limits instrumental function in social and non-verbal communication. What does this study add? A significant percentage of individuals with upper limb loss report significant levels of depression, PTSD, and mixed depression and PTSD. Moreover, women and minority clients were more likely to report clinically significant levels of depression and mixed PTSD and depression. Activity restriction and pain interference's contributions in the final model helped to elucidate the clinical picture of psychological distress for persons with upper extremity limb loss. Greater activity restriction and limitations from pain interference increased the likelihood of reporting clinically significant levels of psychological distress.