This study clinically and molecularly characterizes an adenovirus epidemic that broke out in Taiwan in April 2004. Clinical data on 325 children diagnosed with acute illness were collected between April 2004 and April 2005, and a diagnosis of adenovirus was confirmed by viral isolation. Polymerase chain reaction and restriction fragment length polymorphism were used to identify the adenovirus genotypes in 267 patients. There was a seasonal variation, with a peak incidence between November 2004 and January 2005 (p < 0.001). The median age was 52 months, range 1-210 months. Most cases (90.8%) were younger than 7 years old. Male-to-female ratio was 1.56:1. The most common clinical diagnosis was exudative tonsillitis (50.8%), followed by bronchitis/bronchiolitis (29.9%), conjunctivitis or pharyngoconjunctival fever (22.5%), and acute otitis media (16.3%). Adenovirus type 3 was found in 215 patients (80.5%). The other 52 patients had other genotypes: type 2 (10.1%), type 1 (6.0%), type 5 (1.9%), type 7 (0.7%), type 4 (0.4%), and type 6 (0.4%). Patients with type 3 were significantly older [age >52 months, adjusted odds ratio (OR) 8.55, 95% confidence interval (CI) 1.84-40, p = 0.006), their family members had a higher incidence of illness (adjusted OR 8.77, 95% CI 1.55-50, p = 0.01), they coughed (adjusted OR 6.37, 95% CI 1.54-26.3, p = 0.01), and they had a higher C-reactive protein (CRP) level (>2.87 mg/dL, adjusted OR 3.64, 95% CI 1.06-12.3, p = 0.04) than the 52 cases with other genotypes. In conclusion, this adenovirus outbreak, from late autumn to winter, was predominately caused by adenovirus type 3. Patients with this genotype were significantly older, had a higher incidence of cough and family transmission, and had higher CRP levels than those with other genotypes.