Background The link between chronic exposure to ambient PM2.5and lung cancer is well established. However, there is limited evidence on the effects of more acute, high-level exposure such as that resulting from the 2014 Hazelwood coal mine fire in regional Australia. We investigated the effects of PM2.5from the mine fire on cancer incidence 8.5 years later. Methodology We obtained Victorian Cancer Registry data linked to 2872 Hazelwood Health Study Adult Cohort members, for the period August 2014 to December 2022. Individual fire-related PM2.5exposure was estimated by blending time-location diaries with spatial and temporal air pollution modeling data. To assess the cancer risk associated with fire-related PM2.5exposure, we employed competing risk regression models, accounting for people who died from causes other than cancer during follow-up and adjusting for confounders, including cigarette smoking. Results In the post-mine fire period, 295 people (14.3/1000 person-years) were diagnosed with 332 new cancers (12.7/1000 person-years). No significant association was found between fire-related PM2.5exposure and the overall incidence of cancer (HR = 1.00, 95%CI: 0.90-1.11). Additionally, no associations were identified with any specific cancer subtypes, including lung cancer. However, a higher risk of overall cancer incidence was observed in Morwell compared with Sale (HR = 1.27, 95% CI: 0.93-1.73). Conclusions While we found no evidence that this coal mine fire increased cancer incidence, it would be premature to rule out potential carcinogenic effects. Cancer has a long latency period, which means it will be necessary to analyze new data as they become available to more conclusively determine the effects of medium-duration, high-level smoke exposure.