AbstractIonic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ‐ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ‐ILs in patients with tinea pedis. Thirty‐six enrolled participants were randomized to receive either KCZ‐ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow‐up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ‐ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ‐ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ‐ILs were found to be safe and well‐tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application.