INTRODUCTION: Seasonal influenza is a significant public health challenge worldwide. This study aimed to investigate the epidemiological characteristics and spatial patterns of severe hospitalized influenza cases confirmed by polymerase chain reaction (PCR) in Iran. METHODS: Data were obtained from Iran\'s Ministry of Health and Medical Education and included all hospitalized lab-confirmed influenza cases from January 1, 2016, to December 30, 2018 (n = 9146). The Getis-Ord Gi* and Local Moran\'s I statistics were used to explore the hotspot areas and spatial cluster/outlier patterns of influenza. We also built a multivariable logistic regression model to identify covariates associated with patients\' mortality. RESULTS: Cumulative incidence and mortality rate were estimated at 11.44 and 0.49 (per 100,000), respectively, and case fatality rate was estimated at 4.35%. The patients\' median age was 40 (interquartile range: 22-63), and 55.5% (n = 5073) were female. The hotspot and cluster analyses revealed high-risk areas in northern parts of Iran, especially in cold, humid, and densely populated areas. Moreover, influenza hotspots were more common during the colder months of the year, especially in high-elevated regions. Mortality was significantly associated with older age (adjusted odds ratio [aOR]: 1.01, 95% confidence interval [CI]: 1.01-1.02), infection with virus type-A (aOR: 1.64, 95% CI: 1.27-2.15), male sex (aOR: 1.77, 95% CI: 1.44-2.18), cardiovascular disease (aOR: 1.71, 95% CI: 1.33-2.20), chronic obstructive pulmonary disease (aOR: 1.82, 95% CI: 1.40-2.34), malignancy (aOR: 4.77, 95% CI: 2.87-7.62), and grade-II obesity (aOR: 2.11, 95% CI: 1.09-3.74). CONCLUSIONS: We characterized the spatial and epidemiological heterogeneities of severe hospitalized influenza cases confirmed by PCR in Iran. Detecting influenza hotspot clusters could inform prioritization and geographic specificity of influenza prevention, testing, and mitigation resource management, including vaccination planning in Iran.