OBJECTIVE: To compare the efficacy of chlorfenapyr applied on mosquito nets and as an indoor residual spray against populations of Anopheles gambiae and Culex quinquefasciatus in an area of Benin that shows problematic levels of pyrethroid resistance. METHOD: Eight-week trial conducted in experimental huts. RESULTS: Indoor residual spraying killed 82.9% of An. gambiae overall (mean mortality: 79.5%) compared to 53.5% overall (mean mortality: 61.7%) in the hut containing the lower dosed ITN. Analysis of data on a fortnightly basis showed high levels of mosquito mortality and blood-feeding inhibition during the first few weeks after treatment. Control of C. quinquefasciatus by the IRS and ITN interventions showed a similar trend to that of An. gambiae and though the average level of mortality was lower it was still much higher than with pyrethroid treatments against this population. Chlorfenapyr's reputation for being rather slow acting was evident particularly at lower dosages. The treatments showed no evidence of excito-repellent activity in this trial. CONCLUSION: Chlorfenapyr has the potential to control pyrethroid resistant populations of A. gambiae. There is a need to develop long-lasting formulations of chlorfenapyr to prolong its residual life on nets and sprayed surfaces. On nets it could be combined with a contact irritant pyrethroid to give improved protection against mosquito biting while killing pyrethroid-resistant mosquitoes that come into contact with the net.