Chronic pain and psychiatric conditions have consistently demonstrated substantial overlap in risk factors, epidemiology, and effective treatments. Previous work has identified cross-condition latent factors underlying shared genetic risk for several distinct psychiatric conditions and pain conditions. Here, we sought to examine the relationships between these latent genetic factors to determine biological mechanisms common to both pain and psy-chiatric conditions. We combined two previously published genetic struc-turl equation models. The first model consisted of 24 pain conditions and their two latent factors: General and Musculoskeletal pain-specific. The second model consisted of 11 psychiatric conditions and their four latent factors: Externalizing, Internalizing, Compulsive Thought, and Psychotic Thought. The combined model of six factors and 35 conditions allowed us to estimate correlations between all factors and between conditions of one domain (pain) and factors of the other (psychiatric). We then added three measures of neuroticism (depressive affect subscale, worrying subscale, and total neuroticism score) to this model to examine correlations with all conditions and factors and test for possible explanation of pain-mental disorder relationships by neuroticism. We found that genetic associations between pain and psychiatric conditions were selective to the General Pain factor (and not Musculoskeletal) and Internalizing and Externalizing, but not Thought disorder factors. Neuroticism was associated with pain conditions to the extent that they loaded onto the General Pain factor (i.e., were associated with other pain conditions). Neuroticism also explained a substantial proportion of shared genetic variance between General Pain and Externalizing and between General Pain and Internalizing factors. Overall, the genetic risks shared among chronic pain and psychiatric conditions and neuroticism suggest shared biological mechanisms and underscore the importance of clinical assessment and treatment programs that leverage these commonalities.