Cryotherapy and salicylic acid (SA) often fail as treatments for skin warts. We examined the effectiveness of monochloroacetic acid (MCA) for patients with common or plantar warts. Consecutive patients aged 4 years and older with one or more newly diagnosed common or plantar warts were recruited in 53 Dutch general practices. We randomly allocated eligible patients to 13-week treatment protocols of office-applied MCA versus liquid nitrogen cryotherapy every 2 weeks for patients with common warts (n=188), and MCA versus cryotherapy combined with daily SA self-application for patients with plantar warts (n=227). The primary outcome was the proportion of patients whose warts were all cured at 13 weeks. In the common wart group, cure rates were 40/92 (43%, 95% confidence interval 34-54) for MCA and 50/93 (54%, 44-64) for cryotherapy (risk difference (RD) -10%, -25-4.0, P=0.16). In the plantar wart group, cure rates were 49/106 (46%, 37-56) for MCA and 45/115 (39%, 31-48) for cryotherapy combined with SA (RD 7.1, 5.9-20, P=0.29). For common warts, MCA is an effective alternative to cryotherapy to avoid pain during the treatment, although pain after the treatment is similar. For plantar warts, office-applied MCA may be preferred over cryotherapy combined with SA, on the basis of comparable effectiveness, less treatment pain, and less treatment burden.