Background Long-term exposure to fine particles ≤2.5 μm in diameter (PM 2.5 ) has been linked to cancer mortality. However, the effect of wildfire-related PM 2.5 exposure on cancer mortality risk is unknown. This study evaluates the association between wildfire-related PM 2.5 and site-specific cancer mortality in Brazil, from 2010 to 2016. Methods and findings Nationwide cancer death records were collected during 2010–2016 from the Brazilian Mortality Information System. Death records were linked with municipal-level wildfire- and non-wildfire-related PM 2.5 concentrations, at a resolution of 2.0° latitude by 2.5° longitude. We applied a variant difference-in-differences approach with quasi-Poisson regression, adjusting for seasonal temperature and gross domestic product (GDP) per capita. Relative risks (RRs) and 95% confidence intervals (CIs) for the exposure for specific cancer sites were estimated. Attributable fractions and cancer deaths were also calculated. In total, 1,332,526 adult cancer deaths (age ≥ 20 years), from 5,565 Brazilian municipalities, covering 136 million adults were included. The mean annual wildfire-related PM 2.5 concentration was 2.38 μg/m 3 , and the annual non-wildfire-related PM 2.5 concentration was 8.20 μg/m 3 . The RR for mortality from all cancers was 1.02 (95% CI 1.01–1.03, p < 0.001) per 1-μg/m 3 increase of wildfire-related PM 2.5 concentration, which was higher than the RR per 1-μg/m 3 increase of non-wildfire-related PM 2.5 (1.01 95% CI 1.00–1.01, p = 0.007, with p for difference = 0.003). Wildfire-related PM 2.5 was associated with mortality from cancers of the nasopharynx (1.10 95% CI 1.04–1.16, p = 0.002), esophagus (1.05 95% CI 1.01–1.08, p = 0.012), stomach (1.03 95% CI 1.01–1.06, p = 0.017), colon/rectum (1.08 95% CI 1.05–1.11, p < 0.001), larynx (1.06 95% CI 1.02–1.11, p = 0.003), skin (1.06 95% CI 1.00–1.12, p = 0.003), breast (1.04 95% CI 1.01–1.06, p = 0.007), prostate (1.03 95% CI 1.01–1.06, p = 0.019), and testis (1.10 95% CI 1.03–1.17, p = 0.002). For all cancers combined, the attributable deaths were 37 per 100,000 population and ranged from 18/100,000 in the Northeast Region of Brazil to 71/100,000 in the Central-West Region. Study limitations included a potential lack of assessment of the joint effects of gaseous pollutants, an inability to capture the migration of residents, and an inability to adjust for some potential confounders. Conclusions Exposure to wildfire-related PM 2.5 can increase the risks of cancer mortality for many cancer sites, and the effect for wildfire-related PM 2.5 was higher than for PM 2.5 from non-wildfire sources.