Objectives. To investigate associations between COVID-19-related factors and depressive symptoms among primary care workers (PCWs) in São Paulo, Brazil, and to compare the prevalence of probable depression among PCWs before and during the pandemic. Methods. In a random sample of primary care clinics, we examined 6 pandemic-related factors among 828 PCWs. We used multivariate Poisson regression with robust variance to estimate prevalence ratios for probable depression. We assessed the prevalence of probable depression in PCWs before and during the pandemic in 2 comparable studies. Results. Adjusted prevalence ratios were substantial for insufficient personal protective equipment; experiences of discrimination, violence, or harassment; and lack of family support. Comparisons between PCWs before and during the pandemic showed that the prevalence of probable depression among physicians, nurses, and nursing assistants was higher during the pandemic and that the prevalence among community health workers was higher before the pandemic. Conclusions. Our findings indicate domains that may be crucial to mitigating depression among PCWs but that, with the exception of personal protective equipment, have not previously been examined in this population. It is crucial that governments and communities address discriminatory behaviors against PCWs, promote their well-being at work, and foster family support. (Am J Public Health. 2022;112(5):786–794. https://doi.org/10.2105/AJPH.2022.306723 )