In vivo plasma profiles from formulations containing 5% ibuprofen were compared after a single topical application in a randomised, double-blind, cross-over trial. IbuleveTM gel (Dermal Laboratories, UK) contained only ibuprofen whilst Deep ReliefTM gel (Mentholatum, UK) also contained 3% menthol. In contrast to results obtained when these products were compared under in vitro conditions, there was no statistically significant difference in vivo between delivery of ibuprofen. Estimated relative bioavailability fraction (Deep Relief gel/Ibuleve gel) from log-transformed AUC(0–24h) was 0.99 (95% CI: 0.94–1.04), estimated Cmax ratio was 0.96 (95% CI: 0.91–1.00) and estimated tmax ratio was 1.01 (95% CI: 0.81–1.20). Menthol produces local vasodilation, which reduces skin barrier function, and these data demonstrate that it is inappropriate to extrapolate from in vitro data where formulation components produce biologically-mediated enhancement of permeation which cannot be modelled ex vivo. In clinical use, these products deliver comparable amounts of ibuprofen, but only Deep Reliefgel provides the secondary immediate benefit of the direct analgesic action of menthol.