Objective. To determine the profile of the main caregiver (MC) and the factors associated with her/his care burden, in a multi-centre cohort of patients with multiple pathologies (PMP). Design. Multi-centre cross-sectional study. Setting. Four health districts in the Virgen del Rocio University Hospitals Health Area, Seville, Spain. Participants. The PMP cohort was created by checking all the patients who satisfied the health department criteria for PMP (2002): patients suffering from chronic diseases in 2 or more of the 7 clinical categories defined. Main measurements. The profile of PMP caregiver was determined for all patients. The caregiver strain index (CSI) was determined by the index of care stress (ICS). Predictive factors were analysed by the Student t, ANOVA, and Pearson's tests. Multivariate analysis was performed by a forward stepwise linear regression model. Results. The inter-view was attended by 461 (69%) out of 662 eligible PME Of these, 293 (63.6%) had an MC whose mean age was 62 (15) years; 80% of them were women. First-degree relatives made up 88% of caregivers, with spouses 49.7% of them (n=146). In 41.5%, the CSI was >7 points (mean CSI was 5.35 [3.5]). This was higher in those caring for PMP with neurological illnesses (7 [3.2 vs 4.5 [3.3]; P=.0001). The CSI was compared directly with the medical vulnerability of the PMP (R=0.37; P=.001), cognitive deterioration on the Pfeiffer scale (PS) (R=0.4; P=.0001), and inversely with functional status on Barthel's scale (BS) (R=-0.67; P=.0001). Patient's age (P=.03), his/her medical vulnerability (P=.016) and functional (P<.0001) and cognitive (P=.019) deterioration were independently associated with the CSI. Conclusions. The profile of the MC of the PMP cohort corresponded mainly to firstdegree female relatives around sixty years old. The burden of care was high in more than a third of them. Predictive factors were age, medical vulnerability, and the functional and cognitive deterioration of the PMP.