To evaluate efficacy of monthly administration of selamectin and fipronil against Ctenocephalides felis in cats. Randomized controlled trial. 36 healthy cats. Cats known to be free of fleas were infested with 100 unfed adult fleas on days -28 and -21. On days 0, 30, 60, 90, and 120, sixteen cats (8 pairs/treatment group) were treated by topical administration of selamectin (6 mg/kg [2.7 mg/lb] of body weight) or fipronil (7.5 mg/kg [3.4 mg/lb]). Four control cats (2 pairs) were not treated. On day -6 and every 2 weeks after initial treatment, comb counts were performed to detect fleas. Flea counts were recorded, and fleas (< or =50) that had been removed were replaced onto the cat. On day 89, fleas were not replaced. On day 91 and every 7 days until the end of the study (day 150), cats were challenged with 20 adult fleas. Flea counts were compared between and within treatments. 14 days after treatment, geometric mean flea counts were reduced by 71.2% by fipronil treatment and 35.3% by selamectin treatment. Both treatments resulted in 97 to 98% reduction in flea counts on day 29 and 99.8 to 100% reduction from day 44 to the end of the study. Selamectin is as effective as fipronil in treating infestation in cats housed for 3 months in a flea-infested environment under conditions known to support the flea life cycle and in protecting against subsequent weekly challenges with C felis for an additional 2 months.