Rotavirus vaccination was introduced in high-income countries starting in 2006, with no recommendation for optimal implementation. Economic evaluations were presented before launch projecting potential impacts. Few economic reassessments have been reported following reimbursement. This study compares the short- to long-term economic value of rotavirus vaccination between pre-launch predictions and real-world evidence collected over 15 years, proposing recommendations for optimal vaccine launch. A cost-impact analysis compared rotavirus hospitalisation data after the introduction of vaccination between pre-launch modelled projections and observed data collected in the RotaBIS study in Belgium. A best model fit of the observed data was used to simulate launch scenarios to identify the optimal strategy. Data from other countries in Europe were used to confirm the potential optimal launch assessment. The Belgian analysis in the short term (first 8 years) indicated a more favourable impact for the observed data than predicted pre-launch model results. The long-term assessment (15 years) showed bigger economic disparities in favour of the model-predicted scenario. A simulated optimal vaccine launch, initiating the vaccination at least 6 months prior the next seasonal disease peak with an immediate very high vaccine coverage, indicated important additional potential gains, which would make vaccination very cost impactful. Finland and the UK are on such a route leading to long-term vaccination success, whereas Spain and Belgium have difficulties in achieving optimum vaccine benefits. An optimal launch of rotavirus vaccination may generate substantial economic gains over time. For high-income countries that are considering implementing rotavirus vaccination, achieving an optimal launch is a critical factor for long-term economic success.