Background. Vitamin D analogues are first line treatment options for plaque type psoriasis. One of the drawbacks of therapy with topical Vitamin D analogues is their potential effect on Calcium metabolism. Objective. To determine the safety of ascending doses of Tisocalcitate ointment in healthy male volunteers with special focus on the effects on calcium homeostasis. Methods. Single-center, randomized, double blind, placebo-controlled, dose-escalation, interindividual study to investigate the safety of ascending doses of Tisocalcitate ointment over 14 days under highly standardized study conditions. 8 volunteers were treated with Tisocalcitate ointment and 2 with placebo ointment per dose group. A dose range from 262.5 μg Tisocalcitate/day to 1050 μg Tisocalcitate/day was evaluated. Results. 50 healthy male volunteers (23-45 years of age) were treated for 14 days. All 5 doses (12.5 μg/g Tisocalcitate ointment on 45% BSA, 25 μg/g Tisocalcitate ointment on 30% and 45% BSA, 50 μg/g Tisocalcitate ointment on 30% and 45% BSA) were generally well tolerated. No clinically relevant results of laboratory values were found. Serum calcium was within the normal range for all volunteers during the study. No tendency towards an increase in serum calcium levels or 24-hour urine calcium excretion was observed for any single value or the mean value. There was no change in PTH levels during the study for any volunteer and no serious adverse events were reported. Conclusions. Tisocalcitate ointment, containing a novel Vitamin D analogue, shows an excellent systemic safety profile. There was no tendency towards an effect neither on single values nor on mean values of the calcium metabolism during large area application of Tisocalcitate ointment up to 50 μg/g over 45% BSA in healthy male volunteers.