Abstract: In high-power laser welding, the welding process usually exhibits unstable and defects frequently occurs when higher laser power is used to achieve deeper penetration. At present, it is well recognized that laser welding under vacuum is an effective method to solve the above problems. In this work, a comparison study of weld formation, residual stress and distortion in full-penetration laser welding of medium-thick plates under atmospheric pressure and vacuum was conducted based on a research program of experiment and numerical simulation. The results showed the depth of penetration can be significantly increased by decreasing the ambient pressure, and the required laser power for a 10 mm-thick full-penetration decreased from 10 kW (atmospheric pressure) to 6 kW and a sounder weld quality was obtained under vacuum. The transverse residual stress, longitudinal residual stress and deformation showed a similar distribution under both atmospheric pressure and vacuum. However, the peak values of the residual stress and deformation under vacuum are significantly lower than those for atmospheric pressure due to the lower heat input and the larger depth to width ratio of the weld.