OBJECTIVES: Among individuals who satisfy diagnostic criteria for both major depressive disorder (MDD) and irritable bowel syndrome (IBS), little is known about the role of familial tendency and environmental influences in disease susceptibility. Therefore, we aimed to examine if there is a genetic component to the co-occurrence of MDD and IBS in participants from the population-based Swedish Twin Registry. METHODS: We implemented a nested case-control analysis and a co-twin control analysis. IBS cases were ascertained using an adapted version of the Rome II criteria and MDD cases were assessed using a shortened version of the Computerized International Diagnostic Interview. The case-control analysis included individuals with complete covariate information (N = 29,616), and adjusted for twin pair, 3-yr age band, and sex. The co-twin control analysis considered 288 twin pairs discordant for IBS. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using generalized estimating equations for the case-control analysis and conditional logistic regression for the co-twin control analysis. RESULTS: In all analyses, comorbid disorders of chronic widespread pain, chronic fatigue-like illness, and MDD were more common in IBS cases than controls. In the case-control analysis, individuals with IBS had an increased odds of MDD (OR 2.7, 95% CI 2.3-3.2). In the co-twin analysis, the association was similar (OR 2.2, 95% CI 1.5-3.3) when both MZ and DZ twins were used, and larger among only MZ twins (OR 3.2, 95% CI 1.7-6.1). CONCLUSIONS: From this analysis, we found no evidence that genetic and family environmental factors explain the association between MDD and IBS. Rather, one of these disorders appears to be part of the disease-causing sequence of events, or biologic disease pathway, for the other disorder. However, it was not possible to evaluate the timing of onset between MDD and IBS in this study.