Background: After reaching an all-time low in 2000, syphilis incidence in the United States has increased as the burden shifted from heterosexuals to men who have sex with men (MSM). Houston, Texas, experienced 2 outbreaks of syphilis during this transformation in trends. Further evaluation is necessary to determine if these outbreaks occurred among the same subpopulations. Methods: Surveillance data collected on all reported infectious syphilis cases in Houston from 1971 to 2013 were analyzed. Trends in incidence among MSM and human immunodeficiency virus-positive Houston residents were examined. Peak syphilis years subsequent to 1999, years 2007 and 2012, were compared to determine if outbreaks arose in distinctive subpopulations. Categorical variables between these years were compared using chi-square and Fisher's exact tests, whereas further associations between the years were evaluated using multivariable logistic regression. Results: Incidence among MSM was 20.9 to 32.1 times higher than other men from 2005 to 2013. After adjusting for covariates, cases in 2012 were significantly more likely to be Hispanic (adjusted odds ratio [AOR] = 1.61; 95% confidence interval [95% CI], 1.03-2.53), reported meeting partners via the Internet (AOR, 1.74; 95% CI, 1.18-2.58), and engaged in anonymous sex (AOR, 1.92; 95% CI, 1.40-2.63) in comparison to cases in 2007. Conclusions: We found marked disparities of syphilis by subpopulation in Houston. Herein, we present evidence that outbreaks have been distinct in a major southern city with a high burden of syphilis.