ObjectivesTo investigate gender‐specific factors associated with case complexity in a population‐based sample of middle‐aged and older adults using a holistic approach to complexity.MethodsData were derived from the 8‐year follow‐up home visits of the ESTHER study—a German population‐based study in middle‐aged and older adults. Cross‐sectional analyses were conducted for 2932 persons (aged 57–84). Complexity was assessed by the well‐established INTERMED for the elderly interview, which uses a holistic approach to the definition of case complexity. The association between various bio‐psycho‐social variables and case complexity was analyzed using gender‐specific logistic regression models, adjusted for sociodemographic factors (age, marital status, education).ResultsPrevalence of complexity was 8.3% with significantly higher prevalence in female (10.6%) compared to male (5.8%) participants (p < 0.001). Variables associated with increased odds for complexity in both, women and men were: being divorced (odds ratio [OR] women: 1.86, 95% CI 1.05–3.30; OR men: 3.19, 1.25–8.12), higher total somatic morbidity (women: 1.08, 1.04–1.12; men: 1.06, 1.02–1.11), higher depression severity (women: 1.34, 1.28–1.40; men: 1.35, 1.27–1.44), and higher loneliness scores (women: 1.19, 1.05–1.36; men: 1.23, 1.03–1.47). Women (but not men) with obesity (Body mass index [BMI] ≥30) had higher odds (1.79, 1.11–2.89) for being complex compared to those with a BMI <25. High oxidative stress measured by derivatives of reactive oxygen metabolites in serum was associated with 2.02 (1.09–3.74) higher odds for complexity only in men.ConclusionsThis study provides epidemiological evidence on gender differences in prevalence and factors associated with case complexity in middle‐aged and older adults. Moreover, this study adds to the holistic understanding of complexity by identifying novel variables linked to complexity among middle‐aged and older individuals. These factors include loneliness for both genders, and high oxidative stress for men. These findings should be confirmed in future longitudinal studies.