Cholera is an acute diarrheal disease caused by Vibrio cholerae serogroups O1 and O139, which are known to cause epidemics of cholera in Odisha. The present study was intended to document the antibiotic resistance pattern among clinical isolates of both serogroups of V. cholerae (O1 and O139) isolated during 2004–2013. Nine-hundred nine isolates of V. cholerae were included in this study and were identified by standard procedures. An antibiotic sensitivity test was performed by the disc diffusion method. The seasonality of cholera in this region indicated that there was one peak in the rainy season only. The number of cholera cases started increasing from July and declined starting from the month of October onward. The adult age group of patients was the worst affected among all age groups of patients. The 2 different serogroups of V. cholerae (O1 and O139) showed different prevalence rates (%) of resistance to all the antibiotics in each year. Serogroup O1 showed uniformly high resistance to co-trimoxazole, furazolidone, and nalidixic acid throughout the study. Chloramphenicol encountered resistance only during 2009, but the strains were sensitive in the other years. The emergence of multiple drug-resistant V. cholerae strains may significantly influence the control of future outbreaks and epidemics of cholera in this region.