We tested whether the effect of influenza activity on invasive pneumococcal disease incidence and severity varies between age and comorbidity groups. Weekly rates of invasive pneumococcal disease were obtained from the Danish National Laboratory Surveillance System (1977-2007). Influenza-like illness data were collected from a sentinel surveillance system at the Statens Serum Institut (Copenhagen, Denmark). We fitted Poisson regression models for invasive pneumococcal disease, with predictors of seasonality, trends and influenza activity, and allowed the influenza activity variable to vary by comorbidity level and clinical presentation. Influenza activity accounted for 8.4% (95% CI 4.8-11.9%) and 6.9% (95% CI 5.4-10.2%) of all invasive pneumococcal disease cases among those aged 15-39 and ≥40 years, respectively, but had no measurable impact among children aged <15 years. Influenza activity was associated with significant increases in the incidence of invasive pneumococcal pneumonia in both children and adults. The association was more pronounced among younger adults without comorbidities. Case fatality also varied seasonally among the elderly, and this variation might be associated with influenza activity. Pneumococcal incidence and the severity of disease varied seasonally and between age groups. The effect of influenza activity on pneumococcal disease varied between children and adults, and this difference was largely due to differences in disease presentation.