The "complete cure" of onychomycosis requires long-term treatment with a systemic antifungal agent. Therefore, to properly assess the effects of an antifungal agent on onychomycosis requires a long follow-up. We have conducted a retrospective analysis of the patients treated with griseofulvin (GRF) from 1962 to 1992 and a clinical study to compare the long-term effect of GRF with that of a new oral antifungal agent, itraconazole (ITCZ), for patients who received treatment from 1992 to 1995. For the retrospective study, 281 patients who were microscopically diagnosed as having onychomycosis at the Department of Dermatology, Faculty of Medicine, University of Tokyo, and received GRF administration in 1962, 1972, 1982, and 1992, were evaluated for cure rate and dropout rate. The total cure rate was 29.2%, but the cure rate was 68.8% for the patients who continued their medication for more than one year. For the comparative study, 139 patients who received the treatment at the same institution between 1992 and 1995 were evaluated. The cure rate and the dropout rate for GRF were found to be 23.8% (23/97) and 52.6% (51/97) respectively. The cure rate and the dropout rate for ITCZ were found to be 50.0% (21/42) and 38.1% (15/42). When the two treatment protocols were compared for their long-term effects, we found that most of the patients treated with ITCZ were cured within 3 years, and about 30% of the patients treated with GRF remained uncured even after long-term administration of the agent. Furthermore, from a multiple regression analysis, the GRF/ITCZ administration required to cure onychomycosis was estimated to be 3.92 + 0.161 [Age (years)] + 0.635 [Number of infected toenails] months. The results of this study suggest that the biggest problem associated with the treatment of onychomycosis with an oral antifungal agent is compliance in long-term therapy. Notably, the final cure rate of ITCZ therapy went over 90%, suggesting that the low dose continuous therapy, the standard treatment protocol in Japan, was a key contributing factor for the higher cure rate for ITCZ.