Aims Acute aortic dissection (AD) requires immediate treatment, but is a diagnostic challenge. We studied how often AD was missed initially, which patients were more likely to be missed and how this influenced patient management and outcomes. Methods A retrospective cohort study including 200 consecutive patients with AD as the final diagnosis, admitted to a tertiary hospital between 1998 and 2008. The first differential diagnosis was identified and patients with and without AD included were compared. Characteristics associated with a lower level of suspicion were identified using multivariable logistic regression, and Cox regression was used for survival analyses. Missing data were imputed. Results Mean age was 63 years, 39% were female and 76% had Stanford type A dissection. In 69% of patients, AD was included in the first differential diagnosis; this was less likely in women (adjusted relative risk [aRR]: 0.66, 95% CI: 0.44–0.99), in the absence of back pain (aRR: 0.51, 95% CI: 0.30–0.84), and in patients with extracardiac atherosclerosis (aRR: 0.64, 95% CI: 0.43–0.96). Absence of AD in the differential diagnosis was associated with the use of more imaging tests (1.8 vs. 2.3, p = 0.01) and increased time from admission to surgery (1.8 vs. 10.1 h, p < 0.01), but not with a difference in the adjusted long-term all-cause mortality (hazard ratio: 0.76, 95% CI: 0.46–1.27). Conclusion Acute aortic dissection was initially not suspected in almost one-third of patients, this was more likely in women, in the absence of back pain and in patients with extracardiac atherosclerosis. Although the number of imaging tests was higher and time to surgery longer, patient outcomes were similar in both groups.