Two controlled and masked multi-centre studies were conducted to examine the efficacy of a novel topical avermectin, selamectin, against natural flea infestations on 418 dogs and 345 cats. Veterinary patients with viable flea infestations were enrolled in the studies, which were conducted in United Kingdom, France, Germany, and Italy. Animals were allocated randomly in a 2:1 ratio to one of two treatments: either selamectin alone at a minimum dosage of 6mgkg(-1) or fenthion at recommended dose rates. Concurrent use of an environmental spray (containing methoprene and either pyrethrins or permethrin) was permitted only for fenthion-treated animals. In-contact cats and dogs (animals living in the same home) received the same treatment as the first animal enrolled from the household, if recommended by the veterinarian. Study day 0 was defined as the day of first treatment. Animals were treated on days 0, 30, and 60, and flea comb counts and clinical evaluations were conducted on days 0, 14, 30, 60, and 90. Analysis of variance of ln(flea count+1) showed that values were significantly lower for selamectin alone compared with fenthion (with or without the concurrent use of an environmental spray) in dogs on days 30, 60, and 90 (P<0.05) and in cats on days 14, 30, 60, and 90 (P<0.01). For selamectin, the reductions in geometric mean flea counts on days 14, 30, 60, and 90, compared with day 0, were 92.5, 90.7, 98.1, and 99.1%, respectively, for dogs and 92.8, 92.7, 97.7, and 98.4%, respectively, for cats. Selamectin was shown to be safe and highly effective in the control of naturally acquired flea infestations on dogs and cats presented as veterinary patients in Europe.