Six new 1-alkylazacycloalkan-2-one esters of ketoprofen (1-6) were synthesized and evaluated as potential dermal prodrugs of ketoprofen. Their lipophilicity by both experimental lipophilicity indices (log k') and calculated ClogP was also determined. In vitro experiments were carried out to evaluate the chemical and enzymatic stability and permeation through excised human skin of these new ketoprofen derivatives. Furthermore, we investigated the in vivo topical anti-inflammatory activity of ester 5, which showed the best in vitro profile, evaluating the ability of this compound to inhibit methyl nicotinate-induced skin erythema on healthy human volunteers. Esters 1-6 showed increased lipophilicity compared with the parent drug (ketoprofen), good stability in phosphate buffer pH 7.4, and were readily hydrolyzed by porcine esterase. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 1 and 5 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketoprofen. In vivo results showed an interesting delayed and sustained activity of ester 5, compared with the parent drugs.