To explore the parmacokinetics, safety and tolerability of paclitaxel after oral administration of SMEOF#3, a novel Self-Microemulsifying Oily Formulation, in combination with cyclosporin A (CsA) in patients with advanced cancer. Seven patients were enrolled and randomly assigned to receive oral paclitaxel (SMEOF#3) 160 mg + CsA 700 mg on day 1, followed by oral paclitaxel (Taxol®) 160 mg + CsA 700 mg on day 8 (group I) or vice versa (group II). Patients received paclitaxel (Taxol®) 160 mg as 3-h infusion on day 15. The median (range) area under the plasma concentration-time curve of paclitaxel was 2.06 (1.15-3.47) μg h ml-1 and 1.97 (0.58-3.22) μg h ml-1 after oral administration of SMEOF#3 and Taxol®, respectively, and 4.69 (3.90-6.09) μg h ml-1 after intravenous Taxol®. Oral SMEOF#3 resulted in a lower median Tmax of 2.0 (0.5-2.0)h than orally applied Taxol® (Tmax = 4.0 (0.8-6.1)h, P = 0.02). The median apparent bioavailability of paclitaxel was 40 (19-83)% and 55 (9-70)% for the oral SMEOF#3 and oral Taxol® formulation, respectively. Oral paclitaxel administered as SMEOF#3 or Taxol® was safe and well tolerated by the patients. Remarkably, the SMEOF#3 formulation resulted in a significantly lower Tmax than orally applied Taxol®, probably due to the excipients in the SMEOF#3 formulation resulting in a higher absorption rate of paclitaxel.