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Introduction: Campylobacteriosis, the most common bacterial foodborne illness, infects approximately 1.3 million people in the United States each year. Some Campylobacter infections have antimicrobial resistance to ciprofloxacin and erythromycin, which is a threat to public health given that physicians typically treat severe illnesses with these antimicrobial agents. Aims The objective of this study is to evaluate the change in incidence of Campylobacter over time and describe the trends in resistance to clinically significant antibiotics, including ciprofloxacin and erythromycin. This study will also compare hospitalizations and deaths among patients by resistance to clinically significant antibiotics. Methods A secondary analysis was performed using data from two Centers for Disease Control and Prevention (CDC) surveillance systems: Foodborne Diseases Active Surveillance (FoodNet) and National Antimicrobial Resistance Monitoring System (NARMS). We calculated the incidence of Campylobacter overall and by demographic characteristics for each year and compared resistance to ciprofloxacin and erythromycin in 2005 – 2012 and 2013 – 2017. Chi-Square and Fisher’s Exact tests were used to test differences in resistance over time by demographic characteristics and travel history. Lastly, we assessed health outcomes (hospitalizations and deaths) by antimicrobial susceptibility during 2005 – 2012 and 2013 – 2017. Results During 2005 – 2017, incidence among culture-confirmed Campylobacter infections did not change substantially (12.71/100,000 persons in 2005 and 12.25/100,000 persons in 2017). The highest incidence was found in children younger than 5 years old: 25.24/100,000 persons in 2005 – 2008, 25.47/100,000 persons in 2009 – 2012, 21.92/100,000 persons in 2013 – 2016, and 19.75/100,000 persons in 2017. Notably, males had a higher incidence compared to females across all years. Resistance to ciprofloxacin increased from 24% in 2005 – 2012 to 27% in 2013 – 2017, and resistance to erythromycin increased from 2% in 2005 – 2012 and 3% in 2013 – 2017. Hospitalization was less likely in ciprofloxacin- and erythromycin-resistant cases than in ciprofloxacin- and erythromycin-susceptible cases, and results showed that only 1% of cases died due to infection, irrespective of antimicrobial susceptibility. Discussion The overall incidence and increase in resistance to first-line treatment antibiotics for Campylobacter infections remains a public health concern. The recent data used in our study highlight the importance of conducting Campylobacter surveillance and monitoring antimicrobial resistance.