We evaluated the risk of hospitalization for sickle cell crisis (SCC) following influenza vaccination (trivalent inactivated vaccine, TIV) in adults with sickle cell disease. The cohort consisted of all adults aged 18years and older who had a diagnosis of sickle cell disease in the Vaccine Safety Datalink from 1991 to 2006. The outcome measure was any hospitalization for SCC with the main exposure being influenza vaccine. We used a self controlled case series design to compare the incidence rates of hospitalization for SCC during the exposed and unexposed periods after TIV. No significant association between influenza vaccination and hospitalization for sickle cell crisis was found (IRR ratio 0.92, 95% confidence limits 0.66–1.28). These results provide evidence that the seasonal influenza vaccine is safe as recommended in adults who are at high risk for complications of influenza sequelae due to sickle cell disease.