Background/Objectives: West Nile neuroinvasive disease (WNND) is a severe neurological illness that develops in approximately 1% of individuals infected with West Nile virus (WNV). Manifesting most frequently as encephalitis (WNE), meningitis (WNM), or acute flaccid paralysis (WNP), there is no cure for WNND beyond supportive care and rehabilitation, and death or permanent disability are common outcomes. As the virus arrived in North America less than 20 years ago, determinants of severe disease progression following infection are still being explored. This project is the first to examine comorbid conditions as risk factors of WNND in Ontario using a population-based study design. As prevention is the only avenue of defence against WNND, identifying comorbid risk factors of WNND would allow for public health prevention campaigns targeted to high-risk groups. The main objectives of this thesis were to explore whether pre-existing chronic diseases were associated with the development of WNND, or any of its three manifestations (i.e., encephalitis, meningitis, acute flaccid paralysis). Methods: This was a retrospective, population-based study including all Ontario residents with a confirmed diagnosis of WNV infection between January 1, 2002 and December 31, 2012. A cohort of individuals with WNV was identified from a provincial laboratory database and individually-linked to health administrative databases. In the WNV cohort, individuals with WNND and 13 comorbid conditions were identified using algorithms based on ICD-10-CA diagnostic codes. Incidence of WNND following WNV infection was then compared among individuals with and without comorbid conditions using relative risks estimated by log binomial regression. Additionally, risk ratios were calculated for associations between specific comorbid conditions and WNND neuroinvasive manifestation (i.e., encephalitis, meningitis, acute flaccid paralysis). Finally, associations between Charlson Comorbidity Index (CCI) scoring and development of WNND was examined through calculation of relative risk using log binomial regression. Results/Potential Impact: Risk factors for WNND included male sex (aRR: 1.21; 95% CI: 1.00-1.46) in addition to the combined effect of hypertension and increasing age (5-year intervals) (aRR: 1.16; 95% CI: 1.08-1.24); WNND was also associated with increasing CCI scores; individuals in low, medium, and high categories had increased risk compared to individuals with a score of zero, but the greatest risk was in the high CCI category (aRR: 3.45; 95% CI: 2.25-4.83) Male sex (aRR: 1.32; 95% CI: 1.00-1.76), increasing age (aRR: 1.02; 95% CI: 1.02-1.03), and being immunocompromised (aRR: 2.61; 95% CI: 1.23-4.53) were associated with development of WNE. No risk factors were identified for WNM and WNP. Identification of comorbid risk factors of WNND will allow public health officials to identify high-risk groups and to develop prevention strategies targeted for vulnerable individuals.