Objective: Opposite-direction crashes can be extremely severe because opposing vehicles often have high relative speeds. The most common opposite direction crash scenario occurs when a driver departs their lane driving over the centerline and impacts a vehicle traveling the other direction. In the past 10 years, this cross-centerline crash mode accounts for only 4% of all non-junction crashes but 25% of serious injury crashes of the same type. Lane departure warning systems monitor the position of the vehicle and provide a warning to the driver if they detect the vehicle is moving out of the lane. The objective of this study was to determine the benefits of deploying LDW systems fleet-wide with regards to cross-centerline crashes. Methods: In order to estimate the potential crash reduction beneﬁts of LDW with regards to the cross-centerline crash mode, a comprehensive crash simulation model was developed. The model’s basis was 42 crashes extracted from the NVMCCS database corresponding to 19,467 crashes nationwide. Each crash was simulated in 2 conditions: (1) as it occurred and (2) as if the encroaching vehicle had an LDW system equipped. By comparing the simulated vehicle’s trajectory before and after LDW, the reduction in the probability of a crash was determined. The probability of a crash was summed over all simulations to determine the benefits of an LDW system in preventing cross-centerline crashes. Results: LDW systems could potentially prevent approximately 41.2% of cross-centerline crashes when the vehicle was tracking prior to the crash and a lane line was present. 16.6% of crashes would have a modified impact location possibly resulting in different occupant injuries. The results show that if LDW systems were applied fleet wide, a harmful crash type could be significantly mitigated.