BACKGROUND: To our knowledge, no study has assessed the association between heatwaves and risk of hospitalization and how it may change over time in Brazil. We quantified the heatwave-hospitalization association in Brazil during 2000-2015. METHODS AND FINDINGS: Daily data on hospitalization and temperature were collected from 1,814 cities (>78% of the national population) in the hottest five consecutive months during 2000-2015. Twelve types of heatwaves were defined with daily mean temperatures of ≥90th, 92.5th, 95th, or 97.5th percentiles of year-round temperature and durations of ≥2, 3, or 4 consecutive days. The city-specific association was estimated using a quasi-Poisson regression with constrained distributed lag model and then pooled at the national level using random-effect meta-analysis. Stratified analyses were performed by five regions, sex, 10 age groups, and nine cause categories. The temporal change in the heatwave-hospitalization association was assessed using a time-varying constrained distributed lag model. Of the 58,400,682 hospitalizations (59% women), 24%, 34%, 21%, and 19% of cases were aged <20, 20-39, 40-59, and ≥60 years, respectively. The city-specific year-round daily mean temperatures were 23.5 ± 2.8 °C on average, varying from 26.8 ± 1.8 °C for the 90th percentile to 28.0 ± 1.6 °C for the 97.5th percentile. We observed that the risk of hospitalization was most pronounced for heatwaves characterized by high daily temperatures and long durations across Brazil, except for the minimal association in the north (the hottest region). After controlling for temperature, the association remained for severe heatwaves in the south and southeast (cold regions). Children 0-9 years, the elderly ≥70 years, and admissions for perinatal conditions were most strongly associated with heatwaves. Over the study period, the strength of the heatwave-hospitalization association declined substantially in the south, while an apparent increase was observed in the southeast. The main limitations of this study included the lack of data on individual temperature exposure and measured air pollution. CONCLUSIONS: There are geographic, demographic, cause-specific, and temporal variations in the heatwave-hospitalization associations across the Brazilian population. Considering the projected increase in frequency, duration, and intensity of heatwaves, future strategies should be developed, such as building early warning systems, to reduce the health risk associated with heatwaves in Brazil.