In view of their good skin tolerability, glyceryl fatty acid esters were used as organogelators, and their effects in the topical penetration of piroxicam (Px) were investigated. The in vivo skin penetration was evaluated by measuring the anti-inflammatory effect in rats, where we found that Px incorporated into glyceryl fatty acid ester organogels exhibited a significantly greater inhibition of oedema than that of the placebo control either when applied locally (p < 0.001), or via transdermal absorption (p < 0.01 and < 0.05, respectively). As the Px concentration was increased, the extent of oedema inhibition rose in accordance with a power law. Comparisons with traditional galenic organogels and a marketed product revealed that the relative biological availability of Px was better from glyceryl fatty acid ester organogels, except when calculated for D1 versus T2 and T3. In order to predict the extent of in vivo skin absorption, we measured the penetration coefficient and the in vitro penetration. In accordance with theory, the extent of in vivo oedema inhibition increased as P(oct/w) increased, and maximum inhibition was observed at logP = 2.0211. However, the in vitro penetration through a synthetic membrane did not correlate with the in vivo results, the reason for which might be the different natures of the model barriers.