Purpose: The incidence of Haemophilus influenzae type B (HIB) infection, once the most common cause of periorbital cellulitis, declined dramatically after the introduction of HIB vaccine in 1990. The aim of the current study was to determine the predisposing factors and agents in the pathogenesis of periorbital cellulitis in hospitalized children in the post-HIB vaccination era. Methods: Children with clinical findings of periorbital inflammation who were hospitalized in a tertiary pediatric hospital in Israel in 2000-2001 were observed prospectively. Special attention was directed to the predisposing medical condition in each case. Results: One hundred sixty-three patients had a final discharge diagnosis of periorbital cellulitis. Mean age was 34 months (median = 24 months). The predisposing conditions were conjunctivitis (42.9%), infected wound or trauma (20.9%), insect bites (9.8%), sinusitis (8%), dacryostenosis (4.9%), and Streptococcus pneumoniae bacteremia (0.6%). Children with conjunctivitis and sinusitis had the most severe inflammatory signs. None of the cultures was positive for HIB, although only 71% of the children had complete immunization. Conclusion: The epidemiology of periorbital cellulitis in children has changed in the post-HIB vaccine era. The most common predisposing medical conditions are conjunctivitis or an infected wound in the vicinity of the eye. Bacteremia is rarely a source of the disease. These findings have important clinical implications in terms of choice of treatment.