Background: Smoking may facilitate influenza virus infections and their severity. The objective was to investigate the risk of hospitalization due to influenza in Spanish smokers and ex-smokers. Methods: We carried out a multicentre, case-control study in 2011. Cases [patients ≥ 18 years hospitalized > 24 h with real time polymerase chain reaction (RT-PCR)-confirmed influenza] were selected from 29 Spanish hospitals. For each case, we selected an outpatient aged ≥ 18 years with RT-PCR-confirmed influenza matched by age (±5 years), date of hospitalization of the case (±10 days) and province of residence. We collected epidemiological variables, comorbidities and the smoking history. The risk of hospitalization due to smoking was determined by the adjusted odds ratio (aOR) using logistic regression. Results: We studied 471 hospitalized cases and 476 outpatient cases. Hospitalized cases had a higher frequency of influenza risk factors compared with outpatient cases. Hospitalized cases had a higher frequency of smoking (30.9% vs. 17.1%) and being ex-smokers (29.3% vs. 25.3%). Current smoking (aOR = 2.18, 95% CI: 1.23–3.87) and being an ex-smoker (aOR = 1.73, 95% CI: 1.07–2.82) were associated with the risk of hospitalization. Conclusions: Smoking may increase the risk of hospitalization in smokers and ex-smokers when infected by the influenza virus. Smoking prevention could reduce hospitalizations. Influenza vaccination is recommended for smokers.