Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.