Spinosad 0.9% suspension is a topical treatment for head-lice infestation (pediculosis capitis) that has been approved in the US as a prescription medicine. Spinosad is a natural mixture of the pediculicidal tetracyclic macrolides spinosyn A and spinosyn D. Spinosad 0.9% mainly interferes with nicotinic acetylcholine receptors in insects, thereby producing neuronal excitation that results in paralysis of lice from neuromuscular fatigue after extended periods of hyperexcitation. Spinosad 0.9% kills both permethrin-susceptible and permethrin-resistant populations of lice. It is also ovicidal, killing both eggs (nits) and lice. Systemic absorption was not detectable after a single topical application of spinosad 1.8% for 10 minutes in children. In randomized, evaluator-blind, multicenter clinical trials, topical spinosad 0.9% without nit combing was significantly more effective than permethrin 1% with nit combing in the eradication of head lice assessed 14 days after one or two treatments. The majority of subjects treated with spinosad 0.9% without nit combing required only a single treatment to eradicate head lice, while the majority of those treated with permethrin 1% with nit combing required two treatments. Spinosad was generally well tolerated in clinical trials, with no severe or serious adverse events. Cutaneous and ocular irritation were the most common adverse events.