Background: Premenstrual syndrome (PMS) affects nearly half of women of reproductive age and can substantially impair quality of life, daily functioning, and psychological well-being. Although saffron extract has been proposed as a potential non-pharmacological approach for PMS management, clinical evidence remains limited. This randomized, multicentric, double-blind, placebo-controlled trial evaluated the efficacy and tolerability of saffron extract in reducing PMS symptoms. Methods: A total of 110 healthy women aged 18-45 years with mild-to-moderate PMS were randomized to receive saffron extract (30 mg/day; SafrInside) or placebo for three menstrual cycles. The primary endpoint was the Premenstrual Assessment Form-Short Form (PAF-SF) total score. Secondary endpoints included PAF-SF affect, pain, and water retention subscales, and the Patient Health Questionnaire-4 (PHQ-4) total score. Efficacy analyses were performed in the intention-to-treat (ITT) and per-protocol populations using linear mixed-effects models. Results: Saffron supplementation resulted in a significantly greater reduction in overall PMS symptoms than the placebo (difference in slope for PAF-SF total score: -1.88; 95% confidence interval [CI] -2.64 to -1.12; p