Radiation induced fibrosis is a common side-effect after radiotherapy. Pentoxifylline is reported to reverse radiation injuries when used in conjunction with D-α-tocopherol. However, pentoxifylline has a short half-life, limited oral bioavailability, and induces several systemic adverse effects. The objective of this study was to investigate the feasibility of using Er:YAG fractional laser ablation to enable simultaneous cutaneous delivery of pentoxifylline and D- α -tocopherol succinate from poly(lactide-co-glycolide) microparticles prepared using the freeze-fracture technique. In vitro release experiments demonstrated the different release profiles of the two molecules, which were influenced by their very different lipophilicities and aqueous solubilities. Experiments were then performed to investigate the effect of laser fluence on pore depth and so determine the pore volume available to host the topically applied microparticles. Application of the pentoxifylline and D-α-tocopherol succinate containing microparticles, prepared with RESOMER® RG 502H, to laser porated skin for 48 h, resulted in simultaneous delivery of pentoxifylline (69.63 ± 6.41 μg/cm2; delivery efficiency 46.4%) and D-α-tocopherol succinate (33.25 ± 8.91 μg/cm2; delivery efficiency 22.2%). After deposition into the micropores, the poly(lactide-co-glycolide) microparticles containing pentoxifylline and D-α-tocopherol succinate could serve as an intraepidermal depot to enable sustained drug delivery after micropore closure and thereby reduce the need for repeated microporation.