Cryogen spray cooling is a significant assistance to clinical laser therapy. R134a and R404A are currently used in clinical application and experimental research, which both have extremely high global warming potential (GWP) and serious threat to the environment. An exploratory research was conducted on spray cooling by using R1234yf as an alternative cryogen in clinical application due to its similar properties with R134a and low GWP value. The experimental result on surface heat transfer shows its cooling capacity a little worse than R134a and R404A. The concentration of the spray can be effectively enhanced by reducing the superheat degree, and the surface heat flux can be also enhanced on the premise of flashing atomization, which improves the feasibility of R1234yf spray cooling in clinical application.