Purpose: Cranioplasty is customary after decompressive craniectomy. Many different materials have been developed and used for this procedure. The ideal material does not yet exist, while complication rates in cranioplasties remain high. This study aimed to determine factors related to autologous bone flap failure. Materials and methods: In this two-center retrospective cohort study, 276 patients underwent autologous bone cranioplasty after initial decompressive craniectomy between 2004 and 2014. Medical records were reviewed regarding patient characteristics and factors potentially related to bone flap failure. Data were analyzed using univariable and multivariable regression analysis. Results: Independent factors related to overall bone flap failure were: duration of hospitalization after decompressive craniectomy [OR: 1.012 (95%CI: 1.003–1.022); p = 0.012], time interval between decompressive craniectomy and cranioplasty [OR: 1.018 (95%CI: 1.004–1.032); p = 0.013], and follow-up duration [OR: 1.034 (95%CI: 1.020–1.047); p < 0.001]. In patients with bone flap infection, neoplasm as initial diagnosis occurred significantly more often (29.2% vs. 7.8%; RD 21.3%; 95%CI 8.4 –38.3%; NNH 5; 95%CI 3 –12) and duration of hospitalization after decompressive craniectomy tended to be longer (means 54 vs. 28 days, MD 26.2 days, 95%CI −8.6 to 60.9 days). Patients with bone flap resorption were significantly younger (35 vs. 43 years, MD 7.7 years, 95%CI 0.8–14.6 years) and their cranial defect size tended to be wider than in patients without bone flap resorption (mean circumference 39 vs. 37 cm; MD 2.4 cm, 95% CI -0.43–5.2 cm) and follow-up duration was significantly longer (44 vs. 14 months, MD 29 months, 95%CI 17–42 months). Conclusion: A neoplasm as initial diagnosis, longer hospitalization after decompressive craniectomy, larger time interval between decompressive craniectomy and cranioplasty, and longer follow-up duration are associated with a higher risk of failure of autologous bone flaps for cranioplasty. Patients with these risk factors may be better served with an early recovery program after decompressive surgery or an alloplastic material for cranioplasty.