Objectives: To examine the predictors associated with quality of life of nursing home residents with dementia, in order to identify which predictors are most important and hold most promise for future intervention studies. Methods/Design: This cross-sectional analysis of data collected in two intervention trials included 143 participants with moderate to severe dementia who resided in 40 psychogeriatric wards in 13 nursing homes. The outcome measure quality of life was assessed with the Qualidem. Predictors examined were demographic factors, cognition, mood, behavioral problems, and comorbid conditions. Results: Linear mixed regression analyses showed that all nine domains of quality of life showed independent (negative) associations with either depression, agitation, apathy, or a combination of these predictors. Agitation, apathy, depression, and the presence of neurological disease explained 50% of the variance in total quality of life. Male gender, psychiatric/mood disorders, and having one or more comorbid conditions was associated with worse social relations, while the presence of comorbid neurological diseases was associated with more social isolation and a worse care relationship. The presence of endocrine/metabolic disorders and pulmonary disorders was associated with less restless tense behavior. Conclusions: Different domains of quality of life showed different associations, confirming the multidimensionality of quality of life in nursing home residents with dementia. Quality of life is independently associated with mood and behavioral problems, comorbid conditions, and gender. This knowledge may help to identify older persons at risk of a lower quality of life, and to offer targeted interventions to improve quality of life.