Insect-borne diseases represent a worldwide threat. In addition to fight against vectors (insecticides) and disease prevention (vaccination against yellow fever, chemoprophylaxis against malaria), insect repellents applied on the skin could help reduce the heavy burden related to these diseases. In a field study performed in Senegal, we compared the efficacy of one skin application between 3 and 4 p.m. of four spray repellents [icaridine 20%, para-menthane-diol (PMD) 20% and 50% and DEET 50%] against placebo, among 100 healthy male and female volunteers experienced with mosquito capture. Double-blind randomized cross-over placebo-controlled study (Latin-square design) during five consecutive nights (7 p.m. to midnight) in two villages was conducted. To avoid residual effect, right or left leg was alternately exposed during consecutive nights and the exposed leg was washed before next night. The statistical model was random and mixed effects ANOVA. All four active repellents provided a significant and similar protection compared with placebo, lasting 8 h. However, there was a non-significant trend for a higher protection by DEET 50% than by PMD 20% (P = 0.07). Duration of protection was similar for all repellents. Their effects were similar among men and women, and against Anopheles or other species. No serious adverse drug reaction was noticed. Using a rigorous methodology and a large number of volunteers, our well-controlled study demonstrated an important and similar protective effect of all four repellents compared with placebo. Such field studies should be required before approval of any newly developed repellent.