Aim <p>To test the efficacy of topical application of 5-Fluorouracil in treatment of Odontogenic Keratocyst after enucleation.</p> Materials and Methods <p>Patients diagnosed with OKCs who were randomly allocated into two groups (ten for each case and control group). In the control group Carnoy’s solution was used as an adjuvant method whereas in case group Flonida^TN cream (5% Fluorouracil) was used after cyst enucleation. CBCT was taken for all patients preoperatively and at the 5th ,13th, and 24th week postoperatively. The primary outcome parameters assessed were radiopacity scoring scale, bone growth and increase in bone density. The secondary outcome parameters assessed were pain score, erythema, oedema, lesions, dryness and viscosity. The parameters were compared between case and control group.</p> Results <p>Statistically significant difference was seen between study and control group. 5-FU showed significantly higher bone density (88% vs. 80%, <i>p</i> = 0.026) and radiopacity scores (3 vs. 2) at 24 weeks, with no soft tissue toxicity. Insignificant difference was seen between study and control group in assessing secondary parameters.</p> Conclusion <p>The ease of application of 5-FU with no implications of soft tissue iatrogenic injury can be an ideal alternate substitute for Carnoy’s solution.</p>