This case-control study of proximal humerus fracture included 448 incident female and male cases and 2,023 controls aged 45 years or older identified in five Northern California Kaiser Permanente Medical Centers in 1996–2001. Data were collected by using an interviewer-administered questionnaire. Some factors related to low bone mass, including number of fractures since age 45 years and low dietary calcium intake, were associated with increased risks of fracture, and factors thought to protect against bone loss, such as menopausal hormone therapy and calcium carbonate tablet use, were associated with reduced risks. Fall-related risk factors included previous falls, diabetes mellitus, and difficulty walking in dim light. Possible fall-related risk factors suggested for the first time in this study were seizure medication use (adjusted odds ratio (OR) = 2.80, 95% confidence interval (CI): 1.45, 5.42), depression (OR = 1.34, 95% CI: 0.98, 1.84), almost always using a hearing aid (OR = 1.92, 95% CI: 1.12, 3.31 vs. never prescribed), and left-handedness (OR = 2.36, 95% CI: 1.51, 3.68 vs. right-handedness). Difficulty with activities of daily living and lack of physical activity tended to be associated with increased risk. Prevention of falls among frail, osteoporotic persons would likely reduce the frequency of proximal humerus fracture.