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 the scrotal skin to reduce both the laser power necessary for successful noninvasive laser vasectomy and the probability of scrotal skin burns. A mixture of DMSO/glycerol was noninvasively delivered into the scrotal skin using a Madajet. Near-infrared laser radiation with a range of average powers (7.0-11.7 W) was delivered in conjunction with a range of cryogen spray cooling rates (0.20-0.33 Hz) to the skin surface in a canine model, ex vivo and in vivo. Burst pressure (BP) measurements were conducted to quantify the strength of vas closure. A 30-min application of the OCA improved skin transparency by 26 ± 5 %, reducing the 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 optical clearing agent reduced the laser power necessary for successful noninvasive thermal coagulation of the vas by approximately 25%. This technique may result in the use of a less expensive laser system and eliminate the formation of scrotal skin burns during the procedure.