Objective: To investigate the relationship between the distance of lesions of liver cancer from the liver capsule or subsegmental portal vein branches and intraoperative pain during CT-guided microwave ablation (MWA) under local anesthesia. Methods: Seventy-eight patients with liver cancer undergoing MWA treatment following successful hepatic arterial chemoembolization were selected. According to the primary location of the lesions, they were divided into proximal group (distance between lesions and the liver capsule or subsegmental portal vein branches less than or equal to 5 cm, 32 cases and 37 lesions), and distal group (distance between lesions and the liver capsule or subsegmental portal vein branches more than 5 cm, 46 cases and 54 lesions). The differences of treatment efficacy, degree of intra-procedural pain and other variables between the two groups were compared. Results: The difference in complete tumor ablation rate between proximal group and distal group had no statistical significance (75.86% vs. 81.48%, P>0.05). The AFP levels in both groups were significantly reduced compared with preoperative values (both P<0.05), but no significant inter-group difference was noted (P>0.05). Stratified comparison according to tumor size (≤2 cm and >2 cm) showed that there was no significant difference in VAS score, maximum tolerable dose, and ablation time between the two groups (all P>0.05), but the intraoperative VAS score, relative VAS value and dose of pethidine requirement in proximal group were significantly higher than those in distal group (all P<0.05); the intraoperative VAS score, ablation time and dose of pethidine requirement of patients with tumor size >2 cm in either proximal group or distal group were significantly higher than those of patients with tumor size ≤2 cm (all P<0.05). Conclusion: Pain perception is increased during MWA treatment in liver cancer patients with distance between lesion and the liver capsule or subsegmental portal vein branches ≤5 cm and is especially more obvious in those with tumor diameter larger than 2 cm.