Early influenza activity during the 2012-13 season enabled estimation of the unadjusted effectiveness of the seasonal influenza vaccine. This report presents updated adjusted estimates based on 2,697 children and adults enrolled in the U.S. Influenza Vaccine Effectiveness (Flu VE) Network during December 3, 2012-January 19, 2013. During this period, overall vaccine effectiveness (VE) (adjusted for age, site, race/ethnicity, self-rated health, and days from illness onset to enrollment) against influenza A and B virus infections associated with medically attended acute respiratory illness was 56%, similar to the earlier interim estimate (62%). VE was estimated as 47% against influenza A (H3N2) virus infections and 67% against B virus infections. When stratified by age group, the point estimates for VE against influenza A (H3N2) and B infections were largely consistent across age groups, with the exception that lower VE against influenza A (H3N2) was observed among adults aged ≥65 years. These adjusted VE estimates indicate that vaccination with the 2012-13 influenza season vaccine reduced the risk for outpatient medical visits resulting from influenza by approximately one half to two thirds for most persons, although VE was lower and not statistically significant among older adults. Antiviral medications should be used as recommended for treatment of suspected influenza in certain patients, including those aged ≥65 years, regardless of their influenza vaccination status.