Development of a noninvasive vasectomy technique may eliminate male fear of complications and result in a more popular procedure. This study explores application of an optical clearing agent (OCA) to scrotal skin to reduce laser power necessary for successful noninvasive laser vasectomy and eliminate scrotal skin burns. A mixture of dimethyl sulfoxide and glycerol was noninvasively delivered into scrotal skin using a pneumatic jet device. Near-infrared laser radiation was delivered in conjunction with cryogen spray cooling to the skin surface in a canine model, ex vivo and in vivo. Burst pressure (BP) measurements were conducted to quantify strength of vas closure. A 30-min application of OCA improved skin transparency by 26+/-3%, reducing average power necessary for successful noninvasive laser vasectomy from 9.2 W without OCA (BP=291+/-31 mmHg) to 7.0 W with OCA (BP=292+/-19 mmHg). Control studies without OCA at 7.0 W failed to coagulate the vas with burst pressures (82+/-28 mmHg) significantly below typical ejaculation pressures (136+/-29 mmHg). Application of an OCA reduced the laser power necessary for successful noninvasive thermal coagulation of the vas by approximately 25%. This technique may result in use of a less expensive laser and eliminate the formation of scrotal skin burns during the procedure.