Oseltamivir or zanamivir are effective in outpatients with seasonal influenza; however, factors associated with response have been incompletely described. During the 2008/2009 epidemic, in a randomized trial for influenza A-infected outpatients, clinical (time to alleviation of flu-related symptoms) and virological (rate of patients with day 2 nasal viral load <200 cgeq/µL) responses to oseltamivir or zanamivir were assessed and associated factors were determined using multivariate analysis. For oseltamivir (141 patients) and zanamivir (149 patients) median times to alleviation of symptoms were 3 and 4 days, respectively; 59% and 34% had virological response. For oseltamivir, a lower clinical response was associated with female gender (HR, 0.53; 95% CI, 0.36–0.79), baseline symptoms score >14 (HR, 0.47; 0.32–0.70), viral load ≥5 log cgeq/µL (HR, 0.63; 0.43–0.93), and initiation of antibiotics (HR, 0.30; 0.12–0.76); a lower virological response was associated with female gender (OR, 0.45; 0.21–0.96), baseline viral load ≥5 log cgeq/µL (OR, 0.40; 0.20–0.84) and days 0–2 incomplete compliance (OR, 0.31; 0.10–0.98). For zanamivir, virological response was associated with age ≥50 years (OR, 0.29; 0.10–0.85) and initiation of antibiotics at baseline (OR, 4.24; 1.07–17.50). Factors associated with lower response to neuraminidase inhibitors in outpatients appeared to be easily identifiable during routine clinical examination and, when appropriate, by nasal sampling at baseline. The unknown association between gender and response to oseltamivir was not explained by compliance.