Background: Fatigue has been found to complicate infectious mononucleosis (IM) when patients are directly asked about it. We do not know whether such fatigue is clinically significant, nor whether IM is a specific risk for fatigue (or whether it can follow other common infections). Various risk markers for post-infectious fatigue have been identified, but findings are inconsistent. Aim: To determine the risk of clinically reported fatigue (compared with depression) after IM (compared with both influenza and tonsillitis) in patients attending primary care, and to examine risk markers for post-IM fatigue. Design: Comparison of matched primary-care cohorts. Methods: We identified 1438 adult patients with a positive heterophil antibody test for IM from the UK General Practice Research Database. These patients were individually matched on age, sex and practice to two comparison groups; one with a clinical diagnosis of influenza and the other of tonsillitis. Results: The odds ratios (ORs) (95%CI) for reported fatigue after IM vs. influenza and tonsillitis were 4.4 (2.9–6.9) and 6.6 (4.2–10.4), respectively. Risk markers for post-IM fatigue included female sex and premorbid mood disorder. By comparison, the ORs for depression after IM vs. influenza and tonsillitis were 1.6 (0.9–2.6) and 2.3 (1.4–3.9), respectively. Discussion: IM is a specific and significant risk for clinically reported fatigue, which is both separate from, and more common than, depression. Female sex and premorbid mood disorder are risk markers for fatigue. These can be used both to target prevention strategies and to explore aetiological mechanisms.