After a decompressive craniectomy (DC), a cranioplasty (CP) is often performed in order to improve neurosurgical outcome and cerebral blood circulation. But even though the performance of a CP subsequent to a DC has become routine medical practice, patients can in fact develop many complications from the surgery that could prolong hospitalization and lead to unfavorable prognoses. This study investigates one of the most frequent complications, bone flap infection, in order to identify prognostic factors of its development.In this single-center study, we have retrospectively examined 329 CPs performed between 2002 and 2017. Multiple categorical and metric parameters (e.g., timing of CP, bone flap material, specific laboratory signs of infection and reason for DC) were analyzed applying unadjusted and multivariable testing.Bone flap infection occurred in 24 patients (7.3%). A CP performed more than six months after a DC is associated with a significantly increased risk of infection (OR = 0.308 [0.118; 0.803], p = 0.016). However, with CPs performed after twelve months, the incidence decreases, but without provable statistical impact. In addition, bone flap infection is strongly related to the neurological outcome and the material used for the skull implant, with the use of synthetic bone flaps leading to a marked increase in the rate of infection (p < 0.001).This study supports the hypothesis that the risk of infection is higher the longer the elapsed time between DC and CP, especially if more than six months. Based on our results, the best DC-CP time frame for keeping the infection rate low is performing the CP within the first six months after the DC. In the event that the CP cannot be performed within the first six months, a CP performed twelve months or more after the DC seems to have a favorable outcome as well.