Objective: To explore the roles of ribavirin aerosol in the prevention and treatment of hand-foot-mouth disease (HFMD)., Methods: For this prospective, multicenter, randomized, double-blind and placebo-controlled trial, a total of 300 HFMD outpatients from 3 class 3A hospitals from July 2011 to June 2013 were divided into treatment (ribavirin aerosol) and control (placebo) groups (n = 150 each). The age range was 6 months to 6 years. The proportion of male and female was 1.5: 1. Temperature, herpes of mouth and skin rash were observed before and after treatments. Before treatment and 6-7 days after, their specimens of throat swab were collected and the levels of EV71 and CA16 detected with reverse transcription (RT)-PCR. The software SAS 9.2 was used for statistic data analyses., Results: Before treatment, no significant statistical difference existed in parameters between treatment and control groups (all P > 0.05). After treatment, the degree of herpes of mouth and papulovesicle of skin in treatment group was better than that in control group (100.0% (147/147) vs 83.9% (120/143), χ(2) = 109.21, P < 0.01); (100.0% (147/147) vs 95.9% (139/145) , χ(2) = 6.38, P < 0.05) . The virus negative conversion rates had significant inter-group difference (80.0% (102/110) vs 41.8% (41/98) , χ(2) = 37.06, P < 0.01). The temperature, compliance and differences were not significant (all P > 0.05). The effective rate of comprehensive efficacy in treatment group was higher than that in control group (93.9% (122/130) vs 52.0% (64/123), χ(2) = 111.08, P < 0.01). No obvious adverse drug reaction was observed., Conclusions: Ribavirin aerosol has multiple advantages of lower dose, quicker onset, higher local concentration, better clinical efficacy and fewer side-effects. Its therapeutic effect for local lesion is better than that for systemic lesion. Thus it may shorten the duration of oropharyngeal and skin lesions and lower the number and time of viral release.