Standard catheter-directed thrombolysis (CDT) (S-CDT) is widely accepted as a safer alternative to open surgery for acute limb ischemia (ALI), but data on ultrasound-enhanced CDT (UE-CDT) for limb salvage are limited. This study compares outcomes of UE-CDT versus S-CDT. A 10-year single institution retrospective review identified 68 adult patients who underwent 93 CDT events for ALI, including 62 with UE-CDT and 22 with S-CDT. Following intervention, inpatient, 30 day, and 90 day outcomes were compared; one outcome for comparison was major adverse limb events (MALEs) defined as amputation of any type. No significant differences were observed between UE-CDT and S-CDT in hospital stay (5.6 vs. 7.1 days, P = 0.31), intensive care unit stay (2.5 vs. 2.9 days, P = 0.26), or duration of thrombolysis (24.2 vs. 29.6 hours, P = 0.39). Technical success was achieved in 92% of UE-CDT cases and 95% of S-CDT cases. At 30 days, UE-CDT patients had significantly fewer MALEs compared to S-CDT (6.5% vs. 31.8%; P = 0.01). However, when amputation type was stratified between digit amputation versus above/below knee amputation, there was only a significant difference between digit amputations in the S-CDT compared to UE-CDT at 30 days (P = 0.004). Otherwise, there was no significant difference between the groups at 30 and 90 days when comparing rates of above ankle amputations. UE-CDT and S-CDT for ALI show similar hospital and procedural outcomes. However, UE-CDT is associated with lower 30-day MALE, driven by reduced digit amputations, and becomes nonsignificant when stratifying by above ankle amputations.