In this cross-sectional study, we assess associated factors of burden in spouse-caregivers of patients with acquired brain injury (ABI) in the chronic phase. 35 spouse-caregivers (71% female, mean age ± SD : 55.7 ± 11.1 y) of patients with mild/moderate ABI (29% female, mean age ± SD : 57.5 ± 10.7 y), admitted to the intensive rehabilitation unit of the Institute S. Anna (Crotone, Italy) between January 2013 and December 2017, were contacted 2 years postinjury and asked to complete a series of questionnaires. The outcome measure was the Caregiver Burden Inventory (CBI) test, while several demographical and clinical data were considered as predictive factors. Two years after injury, a high level of burden was reported in 34.2% of spouse-caregivers. Stepwise multiple linear regression analyses revealed that caring for a patient with more severe disability (as measured by the Barthel Index scale) and the family life cycle (from the initial phase of engagement to marriage with adult children) explain the vast majority of variance for higher caregiver burden. The functional clinical status and the stages through which a family may pass over time were identified as areas in which the spouse-caregiver of ABI patients experienced high levels of burden in the chronic phase.