Microbial contamination of contact lenses can be associated with corneal infective or inflammatory events. Hence, there is a need for developing strategies to inhibit microbial adhesion to contact lenses to reduce the incidence of these events. The development of antimicrobial contact lenses is likely to have this effect. Mel4 is an antimicrobial peptide containing 17 amino acids with a + 14 net charge. Previous studies have shown that Mel4-coated lenses are safe in animal and short human clinical trials. However, the efficacy of the Mel4-coated antimicrobial contact lenses in reducing CIEs during extended human wear was unknown. To address this, a prospective, contralateral, double-masked, randomised, controlled clinical trial with extended lens wear was conducted. During this, subjects wore the bi-weekly extended wear lenses for three months, followed by a fourth month no-lens wear follow-up visit. This study determined that Mel4-coated contact lenses could reduce the rate of CIEs by at least 50% compared to uncoated control lenses. However, the reduction was not statistically significant due to the low rate of CIEs observed during the study even in the control eyes. The secondary objectives were to demonstrate safety and biocompatibility, effect on the conjunctival microbiota, and ex-vivo retention of antimicrobial activity. Mel4-coated lenses were safe for extended wear, biocompatible with the ocular surface, and did not change the conjunctival microbiota. The lenses retained antimicrobial activity for a minimum of three days of extended wear. Follow-up studies demonstrated that the loss of activity was probably not due to deposits on lenses but possibly due to the digestion of Mel4 by tear protease, as overnight exposure of Mel4 itself to trypsin abolished its antimicrobial activity. In conclusion, the development of antimicrobial contact lenses is promising to reduce inflammation and possibly infection during contact lens wear.