The extensive use of diesel heavy duty trucks (diesel HDTs) has led to substantial atmospheric pollutant and greenhouse gas (GHG) emissions in Beijing-Tianjin-Hebei-Shandong (BTHS) region, China. The substitution of hydrogen fuel cell heavy duty trucks (HFC-HDTs) for their diesel counterparts is effective to solve the problems above. Aiming at the BTHS region, a GPERF (GHG emission, Pollutant emission and Economic cost Reduction in Fuel cycle) assessment model was established combining with regional vehicle data to investigate the reductions of GHG emissions, pollutant emissions and economic expenditures by the substitution scheme. Data indicated that population of diesel HDTs and HFC-vehicles in BTHS region both accounted for reaching 25% of total in country. Results showed that the fuel substitution scheme could significantly reduce the GHG and pollutant emissions by vehicles in BTHS region, among which the GHG reduced by 1/3, while the NOx and PM remarkably reduced by around 50%.