Permethrin is the most widely used pediculicide, but evidence of resistance from several countries and anecdotal reports from Germany suggest that permethrin lotion is now less effective. We designed a randomized, controlled, parallel group trial involving 100 participants with active head louse infestation to investigate the activity of a coconut and anise spray and to see whether permethrin lotion is still effective, using two applications of product 9 days apart. The spray was significantly more successful (41/50, 82.0%) cures compared with permethrin (21/50, 42.0%; p < 0.0001, difference 40.0%, 95% confidence interval of 22.5% to 57.5%). Per-protocol success was 83.3% and 44.7%, respectively. Thirty-three people reported irritant reactions following alcohol contact with excoriated skin. We concluded that, although permethrin lotion is still effective for some people, the coconut and anise spray can be a significantly more effective alternative treatment.