Influenza immunization rates among children with high-risk medical conditions are disappointingly low, and relatively few data are available on raising rates, particularly over 2 years. We wanted to determine whether interventions tailored to individual practice sites improve influenza immunization rates among high-risk children in inner-city health centers over 2 years. A before-after trial to improve influenza immunization of children was conducted at 5 inner-city health centers (residencies and faith-based). Sites selected interventions from a menu (eg, standing orders, patient and clinician reminders, education) proved to increase vaccination rates, which were directed at children aged 2 to 17 years with high-risk medical conditions. Intervention influenza vaccination rates and 1 and 2 years were compared with those of the preintervention year (2001-2002) and of a comparison site. Influenza vaccination rates improved modestly from baseline (10.4%) to 13.1% during intervention year 1 and to 18.7% during intervention year 2 (P <.001), with rates reaching 31% in faith-based practices. Rates increased in all racial and age-groups and in Medicaid-insured children. The increase in rates was significantly greater in intervention health centers (8.3%) than in the comparison health center (0.7%; P <.001). In regression analyses that controlled for demographic factors, vaccination status was associated with intervention year 1 (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.2) and with intervention year 2 (OR, 2.8; 95% CI, 2.3-3.4), as well as with practice type. Adolescents had lower vaccination rates than children 2 to 6 years old (OR, 0.6; 95% CI, 0.5-0.7). Tailored interventions selected from a menu of interventions modestly increased influenza vaccination rates over 2 years at health centers serving children from low-income families. We recommend this strategy for faith-based practices and residencies with 1 practice site, but further research is needed on multisite practices and to achieve higher influenza vaccination rates.