The 2.1-μn pulsed holmium:yttrium-aluminum-garnet (Ho:YAG) laser combines the properties of transmissibility down a flexible silica fiber, enabling percutaneous or endoscopic use, with high water absorption, suggesting good safety characteristics. Laser attenuation in practice, however, is an extremely complex process. The authors studied its effective penetration through blood, bile, urine, saline, and contrast media.With use of a fiberoptically directed beam and a laser power meter, penetration was measured in vitro with the fiber tip separated from the medium by 5 cm (noncontact mode) and with the fiber tip immersed (contact mode). Logarithm of energy falloff was measured against fluid thickness. Attenuation coefficients (μ) and half value layer (HVL) distances (estimated thickness of fluid needed to halve power) were measured.In noncontact mode, power falloff was exponential. Non-sanguinous media had similar values for μ and HVL (μ = 2.24–2.70 mm −1 and HVL = 0.26–0.31 mm) close to theoretical predictions. Blood caused significantly (P < .05) more attenuation (μ = 5.15 mm −1 , HVL = 0.13 mm). In contact mode, attenuation was much more complex with “plateau” distances of up to 1.2 mm, below which attenuation was negligible. The HVL distances ranged from 0.9 to 1.8 mm and were up to 14 times higher. The main reason is probably the formation of microcavities around the fiber tip.The effective penetration of this laser when immersed may be several times that predicted, with important clinical implications.