AimsTo conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples.MethodsA total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random‐effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies.ResultsFor all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90–99.97] and 98.96 (95% CI = 98.42–99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06–99.62) overall and 96.27% (94.63–97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89–99.99)] overall and 99.93% (99.68–99.98) for bowel cancer screening samples; skin 99.99% (99.92–100.0); renal 99.99% (99.57–100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either.ConclusionsComparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.