Objective To identify the most frequent causes of secondary pseudotumor cerebri syndrome and compare phenotype, clinical presentation, and symptoms of secondary pseudotumor cerebri syndrome to the primary form of pseudotumor cerebri syndrome, idiopathic intracranial hypertension. Methods The study was a prospective cohort study including patients with new-onset pseudotumor cerebri syndrome. Diagnostic work up was standardized. Patients were diagnosed with secondary pseudotumor cerebri syndrome or idiopathic intracranial hypertension according to the revised Friedman criteria. Secondary pseudotumor cerebri syndrome patients were categorized into five causes: medication, systemic causes, sleep apnea, cerebrovascular causes, and several competing causes. Phenotype, clinical presentation, symptoms and neuroimaging were compared between groups. Results Out of 278 cases, 28 secondary pseudotumor cerebri syndrome and 120 idiopathic intracranial hypertension patients were included. The most frequent causes of secondary pseudotumor cerebri syndrome were medication (n  =  8, 28.6%) and systemic causes (n = 8, 28.6%), followed by sleep apnea (n = 5, 17.9%), cerebrovascular causes (n = 4, 14.3%) and several competing causes (n = 3, 10.7%). Secondary pseudotumor cerebri syndrome and idiopathic intracranial hypertension patients were phenotypically alike and predominately female, premenopausal, and obese. Symptoms and objective findings at disease onset were similar between groups. Conclusion Secondary pseudotumor cerebri syndrome should be considered in all patients with suspected pseudotumor cerebri syndrome as secondary pseudotumor cerebri syndrome and idiopathic intracranial hypertension patients are phenotypically and clinically alike. A thorough diagnostic workup is needed as treatment of idiopathic intracranial hypertension and secondary pseudotumor cerebri syndrome is markedly different.