This randomized, evaluator-blind, 3-arm parallel, comparator controlled, multicenter pilot study evaluated the safety and efficacy of ciclopirox nail lacquer topical solution, 8% in combination with oral terbinafine for the treatment of moderate to severe toenail onychomycosis (> or =60% disease involvement of target nail and/or lunula/matrix involvement) (N = 73). Patients were randomized to 1 of 3 treatment arms: ciclopirox nail lacquer once daily for 48 weeks plus 4 weeks of terbinafine 250 mg/day, followed by 4 weeks of rest (no terbinafine), then another 4 weeks of terbinafine 250 mg/day (PLs); ciclopirox nail lacquer once daily for 48 weeks plus terbinafine 250 mg/day for 12 weeks (PL12); or terbinafine 250 mg/day for 12 weeks (L12). At week 48, mycological cure (negative microscopy and culture) occurred in 66.7% (14/21) (PL8), 70.4% (19/27) (PL12), and 56.0% (14/25) (L12) of patients confirmed dermatophyte positive, respectively (P: not significant). At this time point, effective cure (simultaneous mycological cure and > or =90% reduction in the disease area) was observed in 40.0% (8/20), 33.3% (8/24), and 34.8% (8/23) of patients, respectively (P: not significant). The PLs regimen was well-tolerated and had high compliance. The data suggest that combination therapy (PL8) may be an alternative regimen to continuous terbinafine (L12) in the treatment of moderate to severe dermatophyte toenail onychomycosis.