Endometrial cancer (EC) has been associated with an increased risk of cardiovascular disease, including atrial fibrillation (AF). We performed a prospective, case-controlled analysis among 310 Bulgarian women with new-onset, histologically confirmed EC, free of AF at the baseline survey, and women with normal (senile) endometrium/endometrial hyperplasia as a control group ( n = 205). The risk of AF as well as relationship of adiponectin (APN) and high sensitivity C-reactive protein (hs-CRP) levels with AF in women with EC were calculated by Cox proportional hazards models. During the mean follow-up of 2.5 ± 0.5 years, new-onset AF had occurred in 11.7% of women with EC vs. 5.8% in the control group ( p < 0.01). The risk of AF was highest in the first 6 months after new-onset EC, with an incidence rate ratio (IRR) of 1.19 (95% CI 1.10–1.29; p = 0.01). Women with EC, who were obese (body mass index (BMI) > 30 kg/m 2) and younger (age < 60) were found to be more likely to develop AF (HR 1.95; 95% CI 1.18–3.32; p = 0.05). APN levels were not significantly associated with new-onset AF (95% CI 0.87–1.21; p = 0.063). However, the secondary analysis showed evidence of APN–AF association when adjusted for BMI (2.05; 95% CI 1.04–4.04; p = 0.037). We conclude that EC was significantly associated with the incidence of AF.