OBJECTIVES: Previous studies have estimated the risk of death associated with unemployment in the coronavirus disease 2019 (COVID-19) pandemic, but no studies have examined unemployment before COVID-19 infection as a risk factor for COVID-19-related mortality. Thus, this study aimed to investigate COVID-19 mortality among this population. METHODS: Data on 50,038 people aged 25-59 years were collected from 38 agencies in Fars Province, Iran, from February 2020 to July 2021. Follow-up lasted from participants’ diagnosis with COVID-19 based on the results of a reverse transcription-polymerase chain reaction test to participants’ death or the end of the study period. The association between unemployment and COVID-19-related mortality was estimated using the Poisson regression method, and a sensitivity analysis was conducted to calculate the E-value. RESULTS: Unemployment was associated with a 2.41-fold (95% confidence interval [CI], 2.01 to 2.90) higher age-adjusted and sex-adjusted risk of COVID-19-related mortality. The adjusted Poisson regression analysis showed 8.82 (95% CI, 6.42 to 12.11), 2.84 (95% CI, 1.90 to 4.24), and 1.58 (95% CI, 1.24 to 2.01) times higher risks of COVID-19-related mortality among unemployed people aged 25-39 years, 40-49 years, and 50-59 years, respectively, than among their employed counterparts. Unemployment increased the risk of COVID-19 mortality by 3.31 (95% CI, 2.31 to 4.74) and 2.30 (95% CI, 1.86 to 2.84) times in female and male, respectively. The E-value was 3.43, reflecting the minimum strength of confounding required to shift the association between unemployment and COVID-19-related mortality toward the null. CONCLUSIONS Unemployment prior to COVID-19 infection increased the risk of COVID-19-related mortality. COVID-19-related mortality disproportionately impacted unemployed women and younger unemployed people.