Background To date there is no therapy consensus in patients with multifocal hepatocellular carcinoma (mHCC). Purpose To compare outcome of trans-arterial chemoembolization (TACE) with degradable starch microspheres (DSM-TACE) versus selective internal radiation therapy (SIRT) in mHCC. Material and Methods In this single-center study, 36 patients without portal vein invasion, treated between May 2014 and May 2018, were enrolled retrospectively. Eighteen consecutive patients received DSM-TACE and were matched by age, gender, BCLC stage, Child-Pugh status, and tumor volume and 18 patients underwent SIRT. Overall survival (OS), progression-free survival (PFS), and local tumor control (LTC) were evaluated. Toxicity profiles for both therapies were also evaluated and compared. Results In the entire collective, median OS was 9.5, PFS 5.0, and LTC 5.5 months. Subgroup analysis revealed an OS of 9.5 months in both groups ( P = 0.621). PFS was 6 months for the SIRT and 4 months for the DSM-TACE cohort ( P = 0.065). Although not significantly, LTC was lower (4 months) in the SIRT compared to the DSM-TACE cohort (7 months; P = 0.391). When DSM-TACE was performed ≥3 times (n = 11), OS increased, however without statistical difference compared to SIRT, to 11 months, PFS to 7 months, and LTC to 7 months. When DSM-TACE was performed <3 times (n = 7), OS, PFS, and LTC decreased (5 months, P = 0.333; 2 months, P = 0.047; 2 months, P = 0.47). Toxicity profiles and adverse event analysis only revealed a significant difference for nausea and vomiting (more frequent in the SIRT cohort, P = 0.015), while no other parameter showed a significant difference ( P > 0.05). Conclusion DSM-TACE might be an alternative to SIRT in multifocal HCC patients as OS, PFS, and LTC did not differ significantly and toxicity profiles seem to be comparable.