To evaluate safety and effectiveness of the application of piezosurgery in en bloc laminectomy for the treatment of multilevel thoracic ossification of ligamentum flavum (MTOLF). Forty-one cases who had MTOLF and underwent en bloc laminectomy from January 2012 to January 2017 were reviewed and divided into Group A (high-speed drill, n= 23) and Group B (piezosurgery, n=18). Comparisons in clinical outcome and perioperative complications were carried out between the 2 groups. Mean follow-up period was comparable between Group A (12.6 months) and Group B (11.4 months). Both operation time and intraoperative blood loss in Group A were significantly more than those in Group B (P < 0). Although final Japanese Orthopaedic Association (JOA) score in both groups significantly increased, differences in preoperative JOA, final JOA, and neurologic recovery rate between the 2 groups weren't significant. Perioperative complications included early neurologic deterioration (1 in Group A), wound infection (2 in Group A and 1 in Group B), and leakage of cerebrospinal fluid (5 in Group A and 1 in Group B); incidences of these complications between the 2 groups weren't significant (P > 0.05). A relationship analysis showed that cases with preoperative tram track sign, tuberous OLF, or larger compression ratio were at greater risk of developing an intraoperative dura defect. The application of piezosurgery in en bloc laminectomy is a safe and effective method in the treatment of MTOLF, and it was advantageous for reducing both operation time and intraoperative blood loss compared with the high-speed drill.