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STUDY DESIGN A retrospective case-control study. OBJECTIVE This study aimed to compare the effects of the Wiltse approach of pedicle screw fixation (PSF) either in combination with or without vertebroplasty (VP) in the treatment of Genant III degree osteoporotic thoracolumbar fractures (Genant III-OTLFs). METHODS A retrospective study of Genant III-OTLFs was performed from January 2018 to December 2019, including 54 cases of PSF + VP and 56 cases of PSF. Clinical indicators [visual analog scale (VAS) score, Oswestry disability index (ODI)], radiographic parameters [local kyphosis angle (LKA), percentage of anterior, central, and posterior vertebral heights (AVH%, CVH%, and PVH%, respectively)] and follow-up complications [adjacent vertebral fracture (AVF), residual pain (RP), vertebral height loss (VHL), and internal fixation failure (IFF)] were compared between the 2 groups. RESULTS No differences in surgical outcomes, clinical indicators, and radiographic parameters were observed between the 2 groups during the preoperation period and 7 days post-operatively (P > .05). However, the VAS score [2.0 (.6), 1.9 (.5)], ODI [23.7 (4.0), 22.6 (3.0)], LKA [9.5 (1.8), 10.6 (3.0)], AVH% [90.1 (2.7), 87.7 (6.0)], CVH% [92.5 (2.6), 91.3 (3.7)], and PVH% [93.4 (2.0), 92.7 (2.4)] at 1 year post-operatively and last follow-up of the PSF + VP group were better than those of the PSF group [2.5 (.8), 3.1 (1.1), 26.6 (3.8), 29.6 (4.6), 12.2 (1.6), 16.6 (3.2), 84.9 (4.0), 69.9 (6.6), 88.1 (3.1), 78.2 (5.1), 89.7 (2.3), 84.8 (4.6)], respectively (P < .001). During follow-up, the incidence of AVF had no difference (P > .05), while that of RP (32.1 vs 14.8%), VHL (33.9 vs 9.3%) and IFF (17.9 vs 5.6%) had statistical differences between them (P < .05). CONCLUSION The Wiltse approach of PSF combined with VP for Genant III-OTLFs can not only effectively relieve pain, restore vertebral height, and correcte kyphosis, but also better maintain vertebral height, delay kyphosis progression, and reduce complications during follow-up.