Abstract Background In the United States, influenza vaccination is recommended for all children 6 months and older; however, vaccination rates are below target levels. A broad sample of U.S. pediatric offices was assessed to determine factors that influence in-office influenza vaccination rates. Methods Offices (N = 174) were recruited to participate in an observational study over three influenza seasons (2008–2009, 2009–2010, 2010–2011). Only data from the first year of an office’s participation in the study were used. Associations of coverage and 2-dose compliance rates with office characteristics and selected vaccination activities were examined using univariate regression analyses and linear regression analyses using office characteristics identified a priori and vaccination activities with P values ≤0.10 in univariate analyses. Results Influenza vaccination coverage for children 6 months to 18 years of age averaged 25.2% (range: 2.0%–69.1%) and 2-dose compliance for children <9 years of age averaged 53.4% (range: 5.4%–96.2%). Factors associated with increased coverage were non-rural site (P = 0.025), smaller office size (fewer than 5000 patients; P < 0.001), use of evening and weekend hours to offer influenza vaccine (P = 0.004), a longer vaccination period (P = 0.014), and a greater influenza vaccine coverage rate among office staff (P = 0.012). Increased 2-dose compliance was associated with smaller office size (P = 0.001) and using patient reminders (P = 0.012) and negatively related to use of electronic provider reminders to vaccinate (P = 0.003). Conclusions To maximize influenza vaccine coverage and compliance, offices could offer the vaccine during evening and weekend hours, extend the duration of vaccine availability, encourage staff vaccination, and remind patients that influenza vaccination is due. Additional efforts may be required in large offices and those in rural locations.