OBJECTIVE To test the hypothesis that holmium:yttrium-aluminum-garnet (YAG) lithotripsy efficiency varies with stone composition. METHODS Single pulses of holmium:YAG energy were delivered using 272-, 365-, 550-, and 940-microm optical fibers to human calculi composed of calcium oxalate monohydrate (COM), calcium hydrogen phosphate dihydrate (CHPD), cystine, magnesium ammonium phosphate hexohydrate (MAPH), and uric acid. Energy/pulse settings were 0.2, 0.5, 1.0, and 1.5 J. Stone crater width and depth were characterized with reflectance light microscopy. RESULTS For similar energies overall MAPH yielded the deepest and widest craters. CHPD, cystine, and uric acid yielded craters of intermediate width and depth. COM yielded the smallest craters. Within any given composition, increased pulse energy yielded craters of increased width and depth. CONCLUSIONS Holmium:YAG lithotripsy efficiency varies with stone composition. The rank order of crater size appears to correlate with thermal threshold for each composition. Increased holmium:YAG energy produces larger craters for all compositions.