In artificial lesions, improved penetration and the caries-inhibiting properties of infiltrating resins could be observed with increasing penetration coefficients (PCs). The aim of the present study was to compare the penetration abilities of an experimental 'infiltrant' into natural lesions with those of an adhesive in vitro. Extracted human molars and premolars showing proximal white spots were cut across the lesions perpendicular to the surface. Corresponding lesion halves were etched for 120 sec with 15% hydrochloric acid gel and were subsequently treated with either an adhesive (PC: 31 cm/sec) or an infiltrant (PC: 273 cm/sec). Specimens were observed by confocal microscopy and transverse microradiography. Penetration depths of the adhesive were significantly lower compared with those of the infiltrant (p < 0.001; Wilcoxon). It can be concluded that resins with higher PCs (infiltrants) show superior ability to penetrate natural lesions compared with resins with lower PCs.