Splenectomy has been associated with increased risk for infection. To assess the magnitude and duration of risk for hospital contact with infection associated with splenectomy. Population-based cohort study. Denmark. All 3812 persons in Denmark who underwent splenectomy from 1996 to 2005. Splenectomized patients were matched to 3 comparison cohorts: the general population, appendectomized patients, and unsplenectomized patients with indications for splenectomy. Relative risks were assessed for hospital contact involving any infection, pneumonia, and microbiologically confirmed bacteremia among 3812 splenectomized patients and their matched comparisons, during different follow-up periods and after regression analysis for confounder adjustment. The adjusted relative risk for any hospital contact with infection was highest within 90 days of splenectomy: 10.2% vs. 0.6% among general population comparisons (adjusted odds ratio, 18.1 [95% CI, 14.8 to 22.1]) and 10.2% vs. 4.2% among appendectomized patients (adjusted odds ratio, 2.4 [CI, 2.1 to 2.8]). The hazard of infection was 4.6-fold (CI, 3.8 to 5.5) higher in splenectomized patients than in general population comparisons from 91 to 365 days after splenectomy and 2.5 times (CI, 2.2 to 2.8) higher more than 365 days after splenectomy. The risks were similar for pneumonia and were higher for bacteremia. Markedly increased risks were also found when compared with those of appendectomized patients. Modest increases in infection risk were seen with splenectomy matched-indication comparisons (adjusted 90-day odds ratio, 1.7 [CI, 1.5 to 2.1]; hazard ratios, 1.5 [CI, 1.2 to 1.8] from 91 to 365 days after splenectomy and 1.2 [CI, 1.1 to 1.4] beyond 365 days after splenectomy). Relative risks for infection were highest in patients who had splenectomy because of hematologic disorders. Increased surveillance among splenectomized patients may have affected the findings. Splenectomy is associated with increased long-term risk for infections involving hospital contact.