Calcipotriene (CAL) is established to be effective topically in the treatment of psoriasis. Its ability to inhibit proliferation of, and promote differentiation in keratinocytes is usually cited as the mode of action. However, emerging evidence indicates that 1,25-dihydroxyvitamin D 3 and its analogs may also possess important immunomodulatory effects. In a double-blind placebo-controlled study, the early cellular and immunologic events induced by topical CAL were examined in thirty patients with plaque-type psoriasis. Skin biopsies (6 mm) were performed from designated plaques at days 0 (baseline), 3, and 7. On these days and at weeks 2, 4 and 6, complete clinical evaluations were made. The overall scale, erythema, and thickness of psoriatic plaques were graded on a semi-quantitative scale (0 to 8). The biopsy specimens from all 30 subjects were processed for immunohistochemical analyses (CD 1a, CD4, CD8, ICAM, VCAM, ELAM, HLA-DR). From 20 patients, additional skin biopsy specimens allowed for ELISA measurement of cytokines. A significant clinical improvement (p < .05) in psoriasis was observed in patients receiving CAL versus those receiving vehicle (VEH) by day 7 for scale and erythema, and by day 14 for thickness. Continued improvement in these parameters occurred in CAL-treated group throughout the remainder of the study (p < .05 vs. VEH). No significant improvement, however, was seen on day 3. None of the immunohistologic markers semi-quantitatively assessed was significantly affected by 7 days of CAL treatment. In the CAL-treated group, interleukin (IL)-10 level (pg/μg of protein) increased 57% from baseline [0.030±0.006; mean±SEM] to day 3 [0.047±0.011] and remained elevated at day 7 [0.046±0.012] (p = 0.05 vs. baseline; n = 20). IL-8 level, however, declined 70% from baseline [0.13±0.06] to day 3 [0.04±0.01] and remained low at day 7 [0.03±0.02] (p < 0.05 vs. baseline; n = 20). The levels of both IL-8 and IL-10 were unaffected by VEH treatment. IL-10 is a T2 cytokine that antagonizes a T1 dominant state such as in psoriasis, and possesses immunosuppressive activity. IL-8 is a pro-inflammatory cytokine that potently recruits T-cells and neutrophils, and induces angiogenesis. Thus, the net result of IL-10 increase and IL-8 decrease is anti-psoriatic. The modulations of these two cytokines by CAL preceded clinical improvement. Therefore, this reduction in IL-8 and increase in IL-10 may mediate the immunopharmacological improvement of psoriasis caused by CAL.