A new linear interaction energy (LIE) method based on a continuum solvent surface generalized Born (SGB) model is proposed for protein-ligand binding affinity calculations. The new method SGB-LIE is about 1 order of magnitude faster than previously published LIE methods based on explicit solvents. It has been applied to several binding sets: HEPT analogues binding to HIV-1 reverse transcriptase (20 ligands), sulfonamide inhibitors binding to human thrombin (seven ligands), and various ligands binding to coagulation factor Xa (eight ligands). The SGB-LIE predictions and cross-validation results show that about 1.0 kcal/mol accuracy is achievable for binding sets with as many as 20 ligands, e.g., for the HIV-1 RT binding set, RMS errors of 1.07 and 1.20 kcal/mol are achieved for LIE fitting and leave-one-out cross validation, respectively, with correlation coefficients r(2) equal to 0.774 and 0.717. We have also explored various techniques for the LIE underlying conformation space sampling, including molecular dynamics and hybrid Monte Carlo methods, and the final results show that comparable binding energies can be obtained no matter which sampling technique is used.