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Background: Type 2 diabetes Mellitus is a chronic disease, and one of its complications may result in amputation. The goal of this study was to evaluate the impact of psychosocial variables, over time, on quality of life (QoL) of caregivers of patients (N = 110) who had undergone a recent amputation., Method: A longitudinal design was employed: (T1) 1 month after the patient's surgery; (T2) 7 months after; and (T3) 10 months after. Burden Assessment Scale, Family Assessment Device, Revised Impact of Events Scale, Family Disruption from Illness Scale, and Short Form Health Survey were used. A path analysis model was tested., Results: Burden, perception of family functioning, and traumatic symptoms at T1 showed a positive impact on the perception of family functioning, at T2. Traumatic symptoms, at T1, predicted traumatic symptoms at T2 being also a mediator between those symptoms (T1) and physical QoL (T3). Physical and traumatic symptoms, at T1 predicted physical symptoms, at T2 affecting both mental and physical QoL (T3), being also a mediator in these relationships. Burden (T1) also had a direct effect on mental QoL (T3) and at T2 had an impact on physical QoL (T3) mediating also the relationship between burden/physical symptoms at T1 and physical QoL, at T3., Conclusion: Intervention should focus on physical and traumatic symptoms as well as burden since they were both mediators regarding mental and physical QoL., (© 2021. International Society of Behavioral Medicine.)