ABSTRACT Brazil experienced one of the fastest increasing numbers of coronavirus disease (COVID-19) cases worldwide. The Sao Paulo State (SPS) reported a high incidence, particularly in Sao Paulo municipality. This study aimed to identify clusters of incidence and mortality of hospitalized patients with severe acute respiratory syndrome for COVID-19 in the SPS, in 2020–2021, and describe the origin flow pattern of the cases. Cases and mortality risk area clusters were identified through different analyses (spatial clusters, spatio-temporal clusters, and spatial variation in temporal trends) by weighting areas. Ripley’s K12-function verified the spatial dependence between the cases and infrastructure. There were 517,935 reported cases, with 152,128 cases resulting in death. Of the 470,441 patients hospitalized and residing in the SPS, 357,526 remained in the original municipality, while 112,915 did not. Cases and death clusters were identified in the Sao Paulo metropolitan region (SPMR) and Baixada Santista region in the first study period, and in the SPMR and the Campinas, Sao Jose do Rio Preto, Barretos, and Sorocaba municipalities during the second period. We highlight the priority areas for control and surveillance actions for COVID-19, which could lead to better outcomes in future outbreaks. COVID19 COVID 19 (COVID-19 worldwide SPS (SPS municipality COVID-1 20202021 2020 2021 2020–2021 spatiotemporal spatio trends Ripleys Ripley s K12function Kfunction K12 function K infrastructure 517935 517 935 517,93 152128 152 128 152,12 470441 470 441 470,44 357526 357 526 357,52 112915 112 915 112,91 not (SPMR period Campinas Preto Barretos COVID19, 19, outbreaks COVID1 1 (COVID-1 COVID- 2020202 202 2020–202 K1 51793 51 93 517,9 15212 15 12 152,1 47044 47 44 470,4 35752 35 52 357,5 11291 11 91 112,9 (COVID- 202020 20 2020–20 5179 5 9 517, 1521 152, 4704 4 470, 3575 3 357, 1129 112, (COVID 20202 2 2020–2 2020–