Background: Hepatitis C virus (HCV) infections have increased during the past decade but little is known about geographic clustering patterns. Methods: We used a unique analytical approach, combining geographic information systems (GIS), spatial epidemiology, and statistical modeling to identify and characterize HCV hotspots, statistically significant clusters of census tracts with elevated HCV counts and rates. We compiled sociodemographic and HCV surveillance data (n = 99,780 cases) for Massachusetts census tracts (n = 1464) from 2002 to 2013. We used a five-step spatial epidemiological approach, calculating incremental spatial autocorrelations and Getis-Ord Gi* statistics to identify clusters. We conducted logistic regression analyses to determine factors associated with the HCV hotspots. Results: We identified nine HCV clusters, with the largest in Boston, New Bedford/Fall River, Worcester, and Springfield (p < 0.05). In multivariable analyses, we found that HCV hotspots were independently and positively associated with the percent of the population that was Hispanic (adjusted odds ratio [AOR]: 1.07; 95% confidence interval [CI]: 1.04, 1.09) and the percent of households receiving food stamps (AOR: 1.83; 95% CI: 1.22, 2.74). HCV hotspots were independently and negatively associated with the percent of the population that were high school graduates or higher (AOR: 0.91; 95% CI: 0.89, 0.93) and the percent of the population in the "other" race/ethnicity category (AOR: 0.88; 95% CI: 0.85, 0.91). Conclusion: We identified locations where HCV clusters were a concern, and where enhanced HCV prevention, treatment, and care can help combat the HCV epidemic in Massachusetts. GIS, spatial epidemiological and statistical analyses provided a rigorous approach to identify hotspot clusters of disease, which can inform public health policy and intervention targeting. Further studies that incorporate spatiotemporal cluster analyses, Bayesian spatial and geostatistical models, spatially weighted regression analyses, and assessment of associations between HCV clustering and the built environment are needed to expand upon our combined spatial epidemiological and statistical methods.