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Sow mortality has significantly increased throughout the world over the past several years, and it is a growing concern to the global swine industry. Sow mortality increases economic losses, including higher replacement rates, affects employees' morale, and raises concerns about animal well-being and sustainability. This study aimed to assess herd-level risk factors associated with sow mortality in a large swine production system in the Midwestern United States. This retrospective observational study used available production, health, nutritional, and management information between July 2019 and December 2021. A Poisson mixed regression model was used to identify the risk factors and to build a multivariate model using the weekly mortality rate per 1000 sows as the outcome. Different models were used to identify the risk factors according to this study's main reasons for sow mortality (total death, sudden death, lameness, and prolapse). The main reported causes of sow mortality were sudden death (31.22 %), lameness (28.78 %), prolapse (28.02 %), and other causes (11.99 %). The median (25th–75th percentile) distribution of the crude sow mortality rate/1000 sows was 3.37 (2.19 – 4.16). Breeding herds classified as epidemic for porcine reproductive and respiratory syndrome virus (PRRSV) were associated with higher total death, sudden death, and lameness death. Open pen gestation was associated with a higher total death and lameness compared with stalls. Pulses of feed medication was associated with lower sow mortality rate for all outcomes. Farms not performing bump feeding were associated with higher sow mortality due to lameness and prolapses, while Senecavirus A (SVA)-positive herds were associated with a higher mortality rate for total deaths and deaths due to lameness. Disease interactions (herds Mycoplasma hyopneumoniae positive and epidemic for PRRSV; SVA positive herds and epidemic for PRRSV) were associated with higher mortality rates compared to farms with single disease status. This study identified and measured the major risk factors associated with total sow mortality rate, sudden deaths, lameness deaths, and prolapse deaths in breeding herds under field conditions. • Sow mortality rate has increased over the last three years most due to sudden deaths and prolapse deaths. • PRRSV-epidemic status and Mhyo-positive breeding herds reported higher sow mortality. • Pen gestation housing was associated with higher total sow mortality and deaths due to lameness. • The use of whole-herd medication was associated with lower sow mortality rate. • PRRSV epidemic and endemic and SVA-positive herds were associated with a higher sow mortality due to lameness. [ABSTRACT FROM AUTHOR]