Guinea pigs, infected with either Trichophyton mentagrophytes or Microsporum canis, were treated orally or topically with azole antifungals daily for two weeks. Fungi located in the stratum corneum were affected similarly by both treatment schedules, showing typical cell wall changes after azole exposure and necrosis of internal organelles. Fungi located in the hair sheaths were affected only by the oral treatment, which not only prevented invasion of the inner hair structures and inflammatory responses but also led to a complete clearance of the infection within 7 days. Topically applied azole treatment was not able to injure fungi in the hair sheaths and did not suppress invasion into the hair shafts. These observations are in favour of oral antifungal medication with azoles for the treatment of dermatophyte infections involving hairy skin.