Objective. Compare the severity of illnesses associated with influenza and noninfluenza acute respiratory illness (ARI) in healthcare personnel (HCP). Design. Prospective observational cohort. Participants. HCP at 2 healthcare organizations with direct patient contact were enrolled prior to the 2010-2011 influenza season. Methods. HCP who were fewer than 8 days from the start of fever/feverishness/chills and cough were eligible for real-time reverse-transcription polymerase chain reaction influenza virus testing of respiratory specimen. Illness severity was assessed by the sum of self-rated severity (0, absent; 3, severe) of 12 illness symptoms, subjective health (0, best health; 9, worst health), activities of daily living impairment (0, able to perform; 9, unable to perform), missed work, and duration of illness. Results. Of 1,701 HCP enrolled, 267 were tested for influenza, and 58 (22%) of these tested positive. Influenza compared with noninfluenza illnesses was associated with higher summed 12-symptom severity score (mean [standard deviation], 17.9 [5.4] vs 14.6 [4.8]; P < .001), worse subjective health (4.5 [1.8] vs 4.0 [1.8]; P <.05), greater impairment of activities of daily living (4.9 [2.5] vs 3.8 [2.5]; P < .01), and more missed work (12.1 [10.5] vs 7.8 [10.5] hours; P < .01). Differences in symptom severity, activities of daily living, and missed work remained significant after adjusting for illness and participant characteristics. Conclusions. Influenza had a greater negative impact on HCP than noninfluenza ARIs, indicated by higher symptom severity scores, less ability to perform activities of daily living, and more missed work. These results highlight the importance of efforts to prevent influenza infection in HCP.