Background For patients with unresectable colorectal liver metastases (CRLM), clinical guidelines recommend imaging-guided thermal ablation combined with systemic therapy. However, the optimal thermal ablation strategy remains unclear. Purpose To compare long-term outcomes between patients who underwent upfront ablation or delayed ablation for unresectable CRLM. Materials and Methods This retrospective study included patients with unresectable CRLM (three or fewer lesions; diameter, <3 cm) admitted to one of seven hospitals between October 2009 and December 2020. Upfront ablation was performed 2-4 weeks before the start of systemic therapy, and delayed ablation was performed 2-3 months after the start of systemic therapy. Propensity score matching was applied to adjust for differences in baseline variables between groups. Disease-free survival (DFS) was the primary outcome. Overall survival (OS), complications, and adverse events were secondary outcomes. Outcomes were compared between groups by using the log-rank test. Results In total, 255 patients who underwent delayed ablation (mean age, 57 years ± 11 [SD]; 184 men [72%]) and 103 patients who underwent upfront ablation (mean age, 56 years ± 12; 72 men [70%]) were included. After propensity score matching (n = 100 in both groups), the 5-year DFS for patients who underwent upfront ablation was better compared with patients who underwent delayed ablation (36% vs 21%; P = .02). For 5-year OS, no evidence of a difference was observed between ablation strategies (delayed ablation, 59% vs upfront ablation, 64%; P = .49). Additionally, no differences were observed between ablation strategies with respect to the rates of ablative complications (delayed ablation, 6% vs upfront ablation, 5%; P = .76) or drug-related adverse events (delayed and upfront ablation both 9%; P = .99). Conclusion In patients with relatively few (three or fewer) and small (<3 cm) unresectable CRLM, upfront thermal ablation combined with adjuvant systemic therapy led to better DFS compared with delayed ablation. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.