Background: The markedly increased risk of GI cancers after HL is well-established, with GI tumors accounting for the 3rd largest absolute risk of second cancers. However, no large, population-based studies have described overall survival (OS) and cause-specific survival (CSS) of HL survivors who developed GI cancers (HL-GI). Methods: For 209 HL-GI patients (105 colon, 35 stomach, 30 pancreas, 21 rectum, 18 esophagus) and 484,165 patients with first primary GI cancers (GI-1), actuarial OS and CSS were compared, accounting for age, gender, race, SES, GI cancer stage, radiation (RT) for HL, and other variables. Radiation doses to ascending, transverse, and descending colon with standard para-aortic and inverted-Y RT fields were estimated using water and anthropomorphic phantoms. Results: Survival of HL-GI group was inferior compared to GI-1 for most sites (Table). For localized stomach cancer, OS was more than three times worse among HL survivors. Whereas survival of HL patients who developed localized colon cancer (CC) was similar to that of GI-1 group, OS of HL patients with regional or distant CC was reduced 50%. HL survivors with regional or distant CC (transverse segment) had especially high risks of mortality (hazard ratios: 2.7 and 2.6; P=0.001 and 0.002 for OS and CSS respectively). Despite similarities in GI cancer stage between most HL-GI and GI-1 sites, transverse colon cancer was diagnosed at significantly more advanced stages in HL-GI vs. GI-1 (P=0.024). Dosimetry modeling of abdominal RT showed that transverse colon received 81% of total dose (vs. 4-43% to other segments). Conclusions: HL patients who develop GI cancer have significantly reduced survival compared to patients with a first primary cancer in GI sites. Further research is needed to explain the inferior survival of HL patients and to define selection criteria for screening colonoscopies in HL survivors.