To evaluate the safety and efficacy of a novel femtosecond laser-assisted technique for intrastromal administration of riboflavin and higher fluence ultraviolet a (UVA) light in collagen cross-linking (CXL) for keratoconus. Ten eyes with early keratoconus were treated with CXL and followed for a mean of 26 months (range: 18 to 36 months). Using a femtosecond laser, a 100-microm deep, 7-mm diameter intrastromal pocket was created. Two 0.1-mL doses of 0.1% riboflavin solution were infused into the pocket and the cornea was irradiated with 7 mW/cm2 UVA light of mean 370 nm wavelength for 15 minutes. Mean uncorrected visual acuity improved from 20/40.5 to 20/32.5 best spectacle-corrected visual acuity was unchanged at 20/20, mean sphere was reduced by 0.50 diopters (D), mean cylinder was reduced by 0.90 D, and maximum mean keratometry (K) reduced from 48.7 to 47.90 D. No ectasia progression (defined as increase in K over 3-month follow-up) and no statistically significant change in endothelial cell count was noted during follow-up. The mean thinnest corneal thickness appeared to initially reduce but the mean returned to at least the preoperative level by 18 months. All patients returned to full activities within 1 day postoperative. No adverse effects were noted in any of the cases studies. This novel epithelium-sparing, rapid soak-and-treat method of intrastromal riboflavin instillation and higher fluence UVA light for CXL appears to be safe and effective. No negative biomechanical effect (ectasia/epithelial ingrowth) was noted due to the femtosecond laser-created pocket. Because minimal epithelial injury occurs using this technique, postoperative pain appears to be significantly reduced.