The therapeutic efficacy of KP-103, a novel topical triazole, in a guinea pig tinea unguium model was investigated. Experimental tinea unguium and tinea pedis were produced by inoculation of Trichophyton mentagrophytes SM-110 between the toes of the hind paw of guinea pigs. One percent solution (0.1 ml) of KP-103, amorolfine, or terbinafine was topically applied to the nails and whole sole of an infected foot once daily for 30 consecutive days, and terbinafine was also orally administered at a daily dose of 40 mg/kg of body weight for 30 consecutive days, starting on day 60 postinfection. The fungal burdens of nails and plantar skin were assessed using a new method, which makes it possible to recover infecting fungi by removing a carryover of the drug remaining in the treated tissues into the culture medium. Topically applied KP-103 inhibited the development of nail collapse, significantly reduced the fungal burden of the nails, and sterilized the infected plantar skin. On the other hand, topical amorolfine and topical or oral terbinafine were ineffective for tinea unguium, although these drugs eradicated or reduced the fungal burden of plantar skin. The in vitro activities of amorolfine and terbinafine against T. mentagrophytes SM-110 were 8- and 32-fold, respectively, decreased by the addition of 5% keratin to Sabouraud dextrose broth medium. In contrast, the activity of KP-103 was not affected by keratin because its keratin affinity is lower than those of the reference drugs, suggesting that KP-103 largely exists in the nails as an active form that was not bound to keratin and diffuses in the nail without being trapped by keratin. The effectiveness of KP-103 against tinea unguium is probably due to its favorable pharmacokinetic properties in the nails together with its potent antifungal activity.