BACKGROUND: Stigma towards severe mental illness manifests in different ways across cultures and only recently has a theoretical perspective emerged to understand such cultural differences. The 'What Matters Most' framework identifies culturally specific dimensions of stigma by identifying the interactions between cultural norms, roles, and values that impact personhood. OBJECTIVE: This study explores the cultural underpinnings that create and maintain stigmatizing attitudes towards severe mental illness in Chile. METHODS: In-depth interviews developed using the 'Scale of Perceived Discrimination and Devaluation', and the 'What Matters Most' framework were conducted with twenty people identified as having a severe mental illness. Interviews were coded and discussed until agreement was reached, then analyzed by an independent reviewer to determine inter-rater reliability. RESULTS: A key factor shaping stigma among women was the loss of capacity to accomplish family roles (i.e. take care of children).or men, cultural notions of 'Machismo' prevented them from disclosing their psychiatric diagnosis as a means to maintain status and ability to work. A protective factor against stigma for men was their ability to guide and provide for the family, thus fulfilling responsibilities attributable to 'Familismo'. Social appearances could play either a shaping or protecting role,contingent on the social status of the individual. DISCUSSION: In Chilean culture, stigma is rooted in gendered social characteristics and shared familial roles. Interventions should aim to address these norms and incorporate culturally salient protective factors to reduce stigma experienced by individuals with serious mental illness in Chile and other Latin American settings.