In this study, we investigated the weekly reported spatio-temporal distribution and topographic risk factors for Zika virus (ZIKV) infection in northeastern Colombia. Weekly reported surveillance data, including clinical, suspected and confirmed cases from the ongoing ZIKV epidemic in the Santander and Norte de Santander departments (Santanderes) in Colombia were used to estimate cumulative incidence rates. Spatial analysis was performed to develop hot spot maps and to identify spatial topographic risk factors for infection. From January 1, 2016 to March 19, 2016, 11,515 cases of ZIKV were reported in Santanderes, with cumulative rates of 316.07 cases/100,000 population for the region (representing 18.5% of the cases of the country). Five municipalities (four in Norte de Santander) reported high incidence of ZIKV infection (>1,000 cases/100,000 pop); these municipalities are close to the border with Venezuela. Most of the cases reported occurred mainly in low altitude areas, and persistent hot spots were observed. Higher infection rates were reported in the Northeastern part of the study area. Use of risk maps can help guide decisions for the prevention and control of ZIKV. Hotspots on the Colombia-Venezuela border can have implications for international spread.