Background: Tinea pedis, or athlete's foot, is a superficial, skin infection caused by dermatophytes. It is usually topically treated. Nitric oxide is endogenously produced in humans and has a variety of physiologic and antimicrobial properties. SB208 is a novel topical treatment comprising berdazimer sodium (a nitric oxide-storing macromolecule) and a hydrogel. Admixing these two components releases nitric oxide to the application site. Methods: A phase 2, double-blind, randomized trial evaluated the safety and efficacy of 3 doses of SB208 (2%, 4%, and 16%) vs matching vehicle, administered once daily for 14 days, in subjects with culture-confirmed interdigital tinea pedis. The primary efficacy outcome was the proportion of subjects with negative fungal cultures at end of treatment (day 14). Secondary outcomes at days 14 and 42 were the proportion of subjects with mycological cure (negative potassium hydroxide wet mount skin test and culture), clinical cure (reduced signs and symptoms from baseline graded on a 4-point scale). Safety was monitored through physical examinations, adverse events, and hemoglobin and methemoglobin levels. Efficacy outcomes were analyzed using a two-sided Cochran-Mantel-Haenszel test for general association, stratified by site. Results: At day 14, a higher proportion of patients had negative fungal cultures in the pooled SB208-treated group (62%; P=0.04) than the vehicle-treated group (43%). Of SB208 groups, the 4% group had higher incidence of negative fungal cultures vs the vehicle group (67.6% vs 42.9%; P=0.03). At day 42, pooled SB208-treated groups had significantly more mycological cure vs vehicle group (47% vs 31%, respectively; P=0.08), and clinical cure was maintained in 23% of pooled SB208-treated patients vs 14% of vehicle-treated patients. No safety concerns were reported. Adverse events were mild, not serious, and considered unrelated to study medications. Conclusions: Topical SB208 was effective and well tolerated in the treatment of tinea pedis.