BACKGROUND: Long-term exposure to fine particles ≤2.5 μm in diameter (PM2.5) has been linked to cancer mortality. However, the effect of wildfire-related PM2.5 exposure on cancer mortality risk is unknown. This study evaluates the association between wildfire-related PM2.5 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 PM2.5 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 PM2.5 concentration was 2.38 μg/m3, and the annual non-wildfire-related PM2.5 concentration was 8.20 μg/m3. The RR for mortality from all cancers was 1.02 (95% CI 1.01-1.03, p < 0.001) per 1-μg/m3 increase of wildfire-related PM2.5 concentration, which was higher than the RR per 1-μg/m3 increase of non-wildfire-related PM2.5 (1.01 [95% CI 1.00-1.01], p = 0.007, with p for difference = 0.003). Wildfire-related PM2.5 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 PM2.5 can increase the risks of cancer mortality for many cancer sites, and the effect for wildfire-related PM2.5 was higher than for PM2.5 from non-wildfire sources.