Background: Cyclosporin A (CsA) has been shown to be highly effective in the therapy of atopic dermatitis (AD). However, little information exists on the treatment of AD patients with Sandimmun Neoral^® (Neoral), a microemulsion of CsA with improved pharmacokinetic properties in comparison to Sandimmun^®. Objective: We have compared the efficacy and tolerability of Sandimmun and Neoral. Methods: In a randomised, monocentric, double-blind, cross-over pilot study (n = 14), each formulation was administered for 8 weeks, followed by switching to the other treatment group for another 8 weeks. Results: After 2 weeks of therapy, the improvement under Neoral therapy was significantly higher than with Sandimmun (disease activity p = 0.047; extent of disease p = 0.016). In contrast, after 8 weeks of therapy, both formulations yielded similar improvement in the patients’ condition. Conclusion: While both formulations are effective and well tolerated in the treatment of severe AD, Neoral may have a faster onset of action and higher initial efficacy, which makes it an adequate replacement for Sandimmun.