To examine the associations of body mass index (BMI) with serious psychological distress (SPD) after taking into consideration the obesity-related comorbidities (ORCs), lifestyle factors, or emotional support. Self-reported data (n = 153,865) from the 2007 BRFSS were analyzed. Psychological distress was assessed by the Kessler-6 Questionnaire; respondents with a Kessler-6 score of a parts per thousand yen 13 were defined as having SPD. The adjusted prevalence ratios (APRs) with 95 % confidence intervals (CIs) were estimated using log-binomial regression analyses. Overall, 3.2 % of U.S. adults had SPD. The prevalence of SPD was significantly higher among men who were underweight or obese, or among women who were underweight, overweight or obese, compared to those with a normal BMI. The APRs for SPD were 1.58 (95 % CI: 1.06-2.35) in adults who were underweight, and were 1.21 (95 % CI: 1.04-1.41), 1.31 (95 % CI: 1.07-1.61), and 1.36 (95 % CI: 1.13-1.63), respectively, in obese adults with BMI of 30-< 35 kg/m(2), 35-< 40 kg/m(2), and a parts per thousand yen40 kg/m(2) (adults with a normal BMI as the referent). An abnormal BMI is associated with an increased likelihood of having SPD independent of multiple ORCs, lifestyle factors, or emotional support.