Purpose: To investigate the relationship of smoking, urbanicity, and diabetes to presumed ocular histoplasmosis syndrome (POHS) and associated choroidal neovascularization (CNV).Methods: Medical records of 751 adult patients with POHS were reviewed, including 603 patients without CNV and 148 patients with CNV. Age-matched and gender-matched controls were randomly selected from the same practice for comparison. Statistical comparisons of smoking history, urbanicity, and diabetic history were performed using chi-square and conditional logistic regression analyses.Results: Increased rates of current or former smoking, rural residence, and diabetes were found in patients with POHS compared with controls. POHS patients with CNV had increased rates of current or former smoking and rural residence as compared with controls.Conclusion: A history of current or past smoking is associated with an increased risk of developing both POHS alone and POHS with CNV. We did not find a significant additional risk of smoking on the development of CNV in patients with POHS. Patients living in rural locations are more likely than those in urban locations to develop both POHS and POHS with CNV. Diabetics may be more likely to develop POHS than nondiabetics.