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We study the lasting repercussions of the 1918 influenza (‘Spanish Flu’) pandemic on health measures and literacy rates in São Paulo, Brazil, the most populous city in South America today, but significantly poorer a century ago. Leveraging temporal and spatial variation in district-level estimates of influenza-related deaths for the 1917–20 time period, combined with a unique database on demographic and literacy outcomes as well as a detailed set of socio-economic, infrastructure, and regional determinants newly constructed from historical data, we find that the pandemic had significant impacts. In particular, infant mortality and stillbirths rose, sex ratios at birth fell, and there was a marked improvement in male literacy rates for those 15 years and above in 1920. Further analyses reveal that these impacts are most pronounced in districts with older populations, less literate districts, and districts where access to doctors was relatively limited. We find evidence that the male literacy effects persist in 1940. These results highlight that ramifications of the 1918 Spanish Flu pandemic were experienced for at least two decades after the event in a context where institutions were relatively weak and resources for mitigation were limited.