Background <p>Patients undergoing ultrasound-guided percutaneous thermal ablation for hepatocellular carcinoma (HCC) generally experience varying degrees of pain, with significantly more intense sensations particularly during ablation of subcapsular liver lesions. Alfentanil is routinely used for analgesia in brief interventions such as outpatient procedures. This study aimed to compare the median effective dose (ED₅₀) of alfentanil between patients undergoing percutaneous thermal ablation for subcapsular and non-subcapsular HCC.</p> Methods <p>Sixty patients were divided into two groups: Group L (HCC border ≤ 5&#xa0;mm from the hepatic capsule) and Group H (HCC border &gt; 5&#xa0;mm from the hepatic capsule). The initial effect-site concentration of alfentanil was set at 50 ng/mL for the first patient in both groups. Subsequent doses were adjusted using an up-down sequential method, wherein the concentration was increased or decreased by 10 ng/mL based on the previous patient’s response. Effective analgesia was defined as an intraoperative numerical rating scale (NRS) score of &lt; 3 points without involuntary body movement. The ED₅₀ of alfentanil was calculated for both groups using probit regression analysis.</p> Results <p>The ED₅₀ of alfentanil, calculated using probit regression, was 51.7 ng/mL (95% CI, 42.1–61.3 ng/mL) in Group L and 37.4 ng/mL (95% CI, 31.2–42.8 ng/mL) in Group H (<i>P</i> &lt; 0.05).</p> Conclusion <p>In percutaneous thermal ablation, the required dose of alfentanil is significantly higher for subcapsular HCC ablation than for non-subcapsular HCC ablation.</p> Trial registration <p>Registered in the Chinese Clinical Trial Registry (ChiCTR2400093729) on December 11, 2024.</p>