Purpose HCCs bridging two or more Couinaud segments of the liver (watershed tumors) have a higher propensity of recruiting multiple segmental arteries, sometimes recognizable on angiography at the time of TACE or recruited soon after. Our hypothesis is that fewer patients in this subgroup (WS) achieve complete response (CR, mRECIST) after TACE, resulting in more TACE sessions, a shorter time to local recurrence and increased risk of disease progression exceeding Milan criteria for transplant eligibility. Materials and Methods Transplant eligible patients listed with MELD exception points for HCC who underwent TACE as their INITIAL/i> locoregional treatment at our institution were included in this retrospective review. Local response to TACE using mRECIST was recorded for the index tumor or, when other lesions were present, the largest tumor. Time to local recurrence and drop out due to disease progression was recorded in this transplant eligible population. Index tumors treated subsequently with another modality (e.g. ablation) were censored. Results A total of 85 patients (52 WS, 33 non-WS) were identified. Patient demographics and tumor size were similar in both groups. CR was achieved after a single session of TACE in 85% of non-WS tumors compared to 56% of WS tumors (p=0.01). Residual disease treated with additional TACE resulted in subsequent CR in a minority of patients (13% and 3%, WS and non-WS, respectively), while the rest progressed or were treated with an alternative modality. Even following CR after the initial TACE, local recurrence was seen earlier in the WS group (median 337 days) compared to the non-WS group (median 484 days). Finally, tumor progression outside the Milan criteria led to transplant ineligibility in 21% of the patients with WS tumors compared to 12% in the non-WS patients but did not reach statistical significance. Conclusion HCCs located in watershed regions of the liver have a poor response to TACE, requiring multiple TACE sessions. The time to recurrence is shorter and may subsequently lead to transplant ineligibility due to disease progression. Aggressive, possibly multimodality, treatment of these tumors may be warranted.