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Background: We aimed to study age-standardized incidence rates (ASRs) of different cancer sites in Isfahan province, an industrialized city in the central part of Iran. Method: We obtained cancer incidence data from 2014 to 2018 in the Isfahan population-based cancer registry (PBCR). We studied quality indicators of PBCR and the validity of residential places for cancer patients. ASRs per 100,000 of common cancers were reported overall and at subprovincial levels. Results: Overall, 42,994 new cancer cases were registered in Isfahan PBCR in 2014-2018, and 51.4% were male. A high percentage of microscopic verification (MV%) (78.1%) and a low percentage of death certificate-only (DCO%) cases (7%) indicate the acceptable validity and completeness of this registry. The ASRs per 100,000 for all cancers combined were 173.7 in men and 171.1 in women. The most common cancers were prostate (ASR = 26.1), bladder (ASR = 19.9), and colorectum (ASR = 19.6) cancers in men and breast (ASR = 49.9), thyroid (ASR = 11.5), and colorectal (ASR = 15.6) cancers in women. Compared to the national reports in Iran, Isfahan province had a higher ASR of leukemia (13.6 in men and 8.9 in women), non-Hodgkin lymphoma (14 in men and 9 in women), and bladder (19.9 in men and 3.4 in women) cancer. The ASR of childhood cancers was 182.7. Notably, the most frequent cancer was leukemia (ASR = 73.4). We observed a wide geographic heterogeneity of cancer incidence in different counties for some cancers like breast, prostate, leukemia, and colorectal cancers. Conclusion: High incidence rates of hematological malignancies and bladder cancers in Isfahan province suggest further research to study the association between occupational and environmental exposures due to industrial pollution., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Fereshte Lotfi et al.)