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It is essential that healthcare and social professionals understand the daily lives of people with chronic diseases, and the variables that influence them. The aim of this study was to identify the determinants influencing the process of living with long-term conditions. To investigate this, an observational, international, cross-sectional study was carried out. A consecutive sample of 1788 Spanish-speaking population living with chronic obstructive pulmonary disease, chronic heart failure and type 2 diabetes mellitus were included. Descriptive statistics and multiple linear regression models were performed. The linear regression models identified that social support (β = 0.39, p < 0.001) and the satisfaction with life (β = 0.37, p < 0.001) were the main determinants in the process of living with a long-term condition (49% of the variance). Age (β = −0.08, p = 0.01) and disease duration (β = 0.07, p = 0.01) were determinants only in the chronic heart failure subgroup, and country was significant in the chronic obstructive pulmonary disease subgroup (β = −0.15, p = 0.002). Satisfaction with life and social support were key determinants influencing the process of living with long-term conditions. As such, those aspects should be included in the design of interventions focused on the achievement of a positive living in people with long-term conditions.