Cysts are common pathologic entities in the oral and maxillofacial region. Enucleation is commonly used for treatment and is occasionally followed by bone grafting. However, no studies have evaluated factors affecting the failure of grafts used for cystic defects in the oral and maxillofacial region. Therefore, the present study was conducted to determine the risk factors for postoperative graft failure in patients treated with cyst enucleation and simultaneous bone grafting. Clinical data for 305 patients who had undergone cyst enucleation with simultaneous bone grafting were retrospectively investigated in this multicenter case-and-control study. The predictor variables included host, pathologic, and treatment factors. The outcome variable was success or failure of the bone graft. Descriptive statistics were computed, and the P value was set at .05. Bone graft failure was observed in 48 cases. The mean duration from surgery to failure was 38.7days. Multivariable logistic regression analysis showed a significant association between graft failure and younger age (odds ratio [OR]= 1.033; P= .016), smoking (OR= 2.598; P= .017), preoperative infection (OR= 4.660; P= .001), large cysts (OR= 1.052; P= .010), impaction of the mandibular third molar in the cystic cavity (OR= 3.021; P= .007), perilesional osteosclerosis (OR= 4.973; P= .001), and the use of mixed non-autogenous and autogenous bone grafts (OR= 3.891; P= .007). This study provides a list of important factors that should be considered by clinicians planning enucleation and simultaneous bone grafting for cysts in the oral and maxillofacial region.