Influenza and meteorological factors have been associated with increases in the incidence of invasive pneumococcal disease (IPD). However, scant data regarding the impact of influenza and the environment on the clinical presentation of IPD are available. An observational study of all adults hospitalized with IPD was performed between 1996 and 2012 in our hospital. The incidence of IPD correlated with the incidence rates of influenza and with environmental data. A negative binominal regression was used to assess the relationship between these factors. Clinical presentation of IPD during the influenza and non-influenza periods was compared. During the study, 1,150 episodes of IPD were diagnosed. After adjusting for confounding variables, factors correlating with the rates of IPD were the incidence of influenza infection (IRR 1.229, 95% CI 1.025-1.472) and the average ambient temperature (IRR 0.921, 95% CI 0.88-0.964). Patients with IPD during the influenza period had a worse respiratory status. A greater proportion of patients had respiratory failure (45.6% vs 52%, p = 0.032) and higher requirements for ICU admission (19.3% vs 24.7%, p = 0.018) and mechanical ventilation (11% vs 15.1%, p = 0.038). When we stratified by invasiveness of pneumococcal serotypes and the presence of comorbid conditions, the increase in the severity of clinical presentation was focused on healthy adults with IPD caused by nonhighly invasive serotypes. Beyond the increase in the burden of IPD associated with influenza, a more severe clinical pattern of pneumococcal disease was observed in the influenza period. This effect varied according to pneumococcal serotype, host comorbidities, and age.