Background <p>Personal protection with topical skin repellents has been advocated for use against vector-borne diseases. This study compared the efficacies of a 20% IR3535^® lotion with Staytec technology formulation and 25% DEET lotion in repelling mosquitoes in two rural communities in Ghana.</p> Methods <p>Mosquito biting densities were established at baseline and during the intervention using human landing collections (HLC). These were carried out overnight from 21:00–06:00 Greenwich Mean Time (GMT). Prior to the HLC, the exposed legs were treated with either a lotion of the 20% IR3535^® or 25% DEET (as test) at a rate of 1&#xa0;g/600 cm², and 70% ethanol (as control). The sampling (HLC) was performed using the Latin square design. Mosquito species were identified morphologically using some keys and molecularly using polymerase chain reaction (PCR). Evaluations were carried out to determine the knock down resistant (<i>kdr</i>) allele frequencies. The presence of <i>Plasmodium falciparum</i> circumsporozoite proteins was identified using immunological method.</p> Results <p>The major malaria vector observed in the study area was <i>An. gambiae</i> sensu lato (s.l.) with high frequencies of <i>kdr-west</i> mutation in the population. The 20% IR3535^® and 25% DEET treatments reduced mosquito bites by 98% and 95%, respectively, compared with the control (<i>P</i> &lt; 0.01). The collectors were protected by the 20% IR3535^® and 25% DEET for about 92% and 89% of the time, respectively. There was also a sustained protection of the two repellents for 9&#xa0;h. This protection prevented infectious bites in the treatment group compared with the control.</p> Conclusions <p>The 20% IR3535^® with Staytec technology can provide significant protection against <i>Anopheles</i> and other mosquito bites and will be useful for complementing other vector control interventions.</p> Graphical Abstract <p></p>