Background <p>Premenstrual syndrome (PMS) affects around 48% of women of reproductive age worldwide, interfering with psychological and physical well-being as well as functioning. A multitude of interventions exists for PMS, including oral pharmacological interventions, such as antidepressants, combined oral contraceptives, or alternative and complementary interventions. While the use of pharmacological interventions for PMS is linked to multiple side effects, evidence is limited for complementary interventions. Further, placebo effects are high in PMS intervention studies, affecting the estimation of the true treatment effect. An analysis of the relative efficacy between different treatment options is currently lacking, yet urgently needed for clinical decision-making.</p> Methods <p>We plan a network meta-analysis to compare the relative efficacy and safety of oral pharmacological and non-pharmacological interventions for PMS, including all available randomized controlled trials, such as comparator or placebo-controlled trials. Primary outcomes will be symptom intensity and interference; secondary outcomes will be psychological and somatic symptom intensity. Safety will be assessed by the proportion of patients reporting treatment-related adverse events, unwanted events, and by dropouts due to side effects. Published trials will be retrieved from online electronic databases. At least two independent reviewers will screen, select references, and extract data independently. Risk of Bias will be assessed using the Cochrane risk of bias assessment 2 (RoB2) tool. We will conduct a random-effect network meta-analysis within a frequentist framework for each outcome to synthesize all available evidence and compare and rank available oral treatments.</p> Discussion <p>Several interventions are available for PMS, a disabling condition that affects a large proportion of women worldwide. To our knowledge, this will be the first network meta-analysis to synthesize the existing evidence of oral PMS interventions systematically. Comparing the efficacy and safety of all available interventions is necessary to inform clinicians, patients and clinical guidelines to elect the best treatment regimen.</p> Systematic review registration <p>PROSPERO CRD42020214716.</p>