The aim of this study conducted in Spain was to analyze and compare burden, severe burden, and satisfaction among informal caregivers in relation to health-related quality of life (HRQoL), type and duration of caregiving, perceived social support, and use of social and health care services. We performed multivariate analyses to identify variables associated with caregiver burden, severe burden, and satisfaction with caregiving, stratified by gender. The results showed that secondary or third-level education, performance of ungratifying tasks, negative coping with caregiving, and more years providing care were associated with greater burden. Variables with protective effect were better perceived health of the person being cared for, better caregiver HRQoL, and high perceived social support. Women were 75% more likely to experience severe burden compared with male caregivers. Burden was reduced by high perceived social support in the case of women and by high caregiver HRQoL in the case of men. The main determinant of caregiving satisfaction for both men and women was perceived social support (OR = 3.11 and OR = 6.64). This study shows the need for interventions that promote gender equality and social support as a means of relieving burden and severe burden and improving satisfaction in both male and female caregivers.