Spironolactone (SP) known as an anti-androgen drug, has been proven to be effective in treatment of acne. The quest to minimize the unnecessary systemic side effects associated with the oral drug admin- istration of spironolactone, has led to a growing interest of loading SP on lipid nanoparticles to deliver the drug in a topical formulation. The aim of the current investigation was to prepare and compare the performance of SP loaded nanostructured lipid carrier (SP-NLC) and SP alcoholic gels (SP-ALC) on two groups of respective patient populations, group A and group B in the treatment of mild to moderate acne vulgaris. The results showed that SP-NLCs were spherical in shape with an average diameter of ∼240 nm. The polydispersity index (PI) and zeta potential of these nanoparticles were 0.286 and −21.4 respectively. The gels showed non-Newtonian independent pseudoplastic and shear thinning behavior. The SP-NLCs was not toxic to fibroblast cell strains at the 24 and 48 h periods. Results showed that the mean number of total lesions (37.66 ± 9.27) and non-inflammatory lesions (29.26 ± 7.99) in group A sig- nificantly decreased to 20.31 ± 6.58 (p < 0.05) and to 13.95 ± 5.22 (p < 0.05) respectively. A similar pattern was observed for group B where the mean number of total lesions and non-inflammatory lesions reduced from 33.73 ± 9.40 to 19.13 ± 5.53 (p < 0.05) and from 25.65 ± 8.12 to 13.45 ± 4.48 (p < 0.05) respectively. The total lesion count (TLC) was significantly decreased from 37.16 ± 9.28 to 19.63 ± 6.36 (for group A; p < 0.071) and 32.60 ± 9.32 to 18.33 ± 5.55 (for group B; p < 0.05) respectively. After treatment with SP- NLC for 8 weeks, the water content of the skin significantly (p