Objective To explore the effect of three skin-expansion methods applied to cancer patients for advancement of sheath in PICC insertion under modified Seldinger technique. Methods A total of 384 cancer patients to receive PICC insertion were selected and randomly divided into 3 groups,128 cases in each group. In group A, the PICC introducer sheath was inserted by blunt separation approach (the soft-tissue dilator and the outer sheath of traditional puncture needle were assembled prior to sheath insertion). In group B, the PICC introducer sheath was inserted by blunt separation which was performed with the soft-tissue dilator and the introducer sheath components. In group C, the PICC introducer sheath was inserted by expanding the skin with an expanding knife. One-time success rate of PICC introducer sheath insertion, incidence rates of blood oozing and exudate at the puncture site 24 h into catheterization as well as Visual Analogue Score (VAS) for pain during catheter insertion were compared among the three groups. Results One-time success rate of PICC introducer sheath insertion in group A and group C were both 100%, versus 95.31% in group B. The incidence rates of blood oozing and exudate at the puncture site 24 h into catheterization had significant differences among the 3 groups (P<0.01 for both), with group A and group B significantly lower than group C. Pain scores during catheter insertion in group A and group B were lower than group C. Conclusion The method of PICC introducer sheath insertion by blunt separation approach after assembling the soft-tissue dilator and the outer sheath of traditional puncture needle not only improves one-time success rate of sheath insertion, but also reduce the rate of blood oozing of and exudate at the puncture site and pain levels during catheterization.