OBJECTIVE: To determine the proportion of correct emergency department (ED) diagnoses and of hospital discharge diagnoses, in comparison with final diagnoses at the end of a 30-day follow-up, in patients presenting with nonspecific complaints (NSCs) to the ED; to determine differences between male and female patients in the proportion of missed diagnoses. METHODS: Prospective observational study. Diagnoses made at the ED, hospital discharge diagnoses, and final diagnoses were compared. RESULTS: Of 22,782 nontrauma patients presenting to the ED from May 2007 until May 2009, 9,926 were triaged as emergency severity index level 2 or 3, of whom 789 presented with NSCs. After exclusion of 217 patients, 572 were included for final analysis. The final diagnosis at the end of follow-up was taken to be the correct "gold standard" diagnosis. In 263 (46.0%) patients, this corresponded to the primary ED diagnosis, and in 292 (51%) patients to the hospital discharge diagnosis. The most frequent final diagnoses were urinary tract infections (n = 49), electrolyte disorders (n = 40) and pneumonia (n = 37), and were correctly diagnosed at the ED in 23, 21 and 27 patients, respectively. Of the twelve most common diagnoses (corresponding to 354 patients), functional impairment was most frequently missed. Among these 354 patients, diagnoses were significantly more often missed in women than in men (142 of 231 [62%] women vs 57 of 123 [46%] men, p = 0.004). CONCLUSION: Patients presenting to the ED with NSCs present a diagnostic challenge. New diagnostic tools are needed to help in the diagnosis of these patients.ClinicalTrials.gov registration number: NCT00920491