Background and Aims: An increased risk of small bowel carcinoma [SBC] has been reportedin coeliac disease [CD] and Crohn’s disease [CrD]. We explored clinico-pathological, molecular,and prognostic features of CD-associated SBC [CD-SBC] and CrD-associated SBC [CrD-SBC] incomparison with sporadic SBC [spo-SBC].Methods: A total of 76 patients undergoing surgical resection for non-familial SBC [26 CD-SBC,25 CrD-SBC, 25 spo-SBC] were retrospectively enrolled to investigate patients’ survival andhistological and molecular features including microsatellite instability [MSI] and KRAS/NRAS,BRAF, PIK3CA, TP53, HER2 gene alterations.Results: CD-SBC showed a significantly better sex-, age-, and stage-adjusted overall and cancerspecificsurvival than CrD-SBC, whereas no significant difference was found between spo-SBCand either CD-SBC or CrD-SBC. CD-SBC exhibited a significantly higher rate of MSI and mediantumour-infiltrating lymphocytes [TIL] than CrD-SBC and spo-SBC. Among the whole SBC series,both MSI─which was the result of MLH1 promoter methylation in all but one cases─and high TILdensity were associated with improved survival at univariable and stage-inclusive multivariableanalysis. However, only TILs retained prognostic power when clinical subgroups were added tothe multivariable model. KRAS mutation and HER2 amplification were detected in 30% and 7% ofcases, respectively, without prognostic implications.Conclusions: In comparison with CrD-SBC, CD-SBC patients harbour MSI and high TILs morefrequently and show better outcome. This seems mainly due to their higher TIL density, which atmultivariable analysis showed an independent prognostic value. MSI/TIL status, KRAS mutationsand HER2 amplification might help in stratifying patients for targeted anti-cancer therapy.