To investigate if there is a synergy between the presence of the Malassezia yeasts and the adverse reaction during treatment of scalp psoriasis with calcipotriol scalp solution, patients were treated with itraconazole to reduce the number of Malassezia yeasts. This study was a double-blind, placebo-controlled parallel group study between oral itraconazole or placebo for 8 weeks in patients with scalp psoriasis. After 2 weeks, calcipotriol scalp solution was applied twice daily for 6 weeks. Altogether 137 patients, 67 in the itraconazole group and 70 in the placebo group, comprised the intention-to-treat population. There were 13 (19.4%) patients with local skin irritation in the itraconazole group compared to 33 (47.1%) in the placebo group (p < 0.001). The skin irritation was significantly lower in patients with a low number of cultured Malassezia yeasts (p = 0.017). Thus, when Malasessia was eliminated or the numbers reduced, the irritation produced by calcipotriol was significantly diminished.