Background: Two-stage hepatectomy (TSH) is the present standard for multiple bilobar colorectal metastases (CLM). As alternative, ultrasound-guided one-stage hepatectomy (E-OSH) has been proposed even for deep-located nodules to compare TSH and E-OSH. Methods: All consecutive TSH at the Paul Brousse Hospital and E-OSH at the Humanitas Research Hospital were considered. The inclusion criteria were ≥6 CLM, ≥3 CLM in the left liver, and ≥1 lesion with vascular contact. A total of 74 TSH and 35 E-OSH were compared. Results: The 2 groups had similar characteristics. Drop-out rate of TSH was 40.5%. In comparison with the cumulated hepatectomies of TSH, E-OSH had lower blood loss (500 vs. 1,100 mL, p = 0.009), overall morbidity (37.1 vs. 70.5%, p = 0.003), severe morbidity (14.3 vs. 36.4%, p = 0.04), and liver-specific morbidity (22.9 vs. 40.9%, p = 0.02). R0 resection rate was similar between groups. E-OSH and completed TSH had similar overall survival (5-year 38.2 vs. 31.8%), recurrence-free survival (3-year 17.6 vs. 17.7%), and recurrence sites. Conclusions: E-OSH is a safe alternative to TSH for multiple bilobar deep-located CLM. Whenever feasible, E-OSH should even be considered the preferred option because it has excellent safety and oncological outcomes equivalent to completed TSH, without the drop-out risk.