OBJECTIVE: To examine self-harm risk across the adult age range in patients diagnosed with various physical illnesses using the General Practice Research Database - a broadly representative sample of all people registered with a family practice in the United Kingdom. METHODS: We conducted a large nested case-control study sampled from the whole primary care cohort. During 2001-2008 we studied 2306 cases of self-harm and 46,120 age and gender-matched controls without such an episode recorded. Relative risks were estimated against reference patients with none of the examined physical illnesses. Additionally, we assessed confounding by recorded depression, effect modification by gender and multi-morbidity effects. RESULTS: Risk was significantly elevated in relation to any of the physical illnesses (male OR 1.35, 95% CI 1.18-1.54; female OR 1.62, 95% CI 1.40-1.86). For both genders combined, risk was raised with each specific illness. Effects sizes were consistently larger in women. Adjustment for recorded depression explained much of the elevated risk, but not so in women with asthma, back pain, diabetes, epilepsy or hypertension. Raised risk was seen in younger adults and during middle age, but not among older people. There was a dose-response relationship with increasing number of physical illnesses, and in women this was independent of depression. CONCLUSION: Heightened risk was seen with a variety of physical illnesses. The findings indicate a need for tackling psychological distress and reducing self-harm risk in physically ill patients who attend primary healthcare services for non-psychiatric reasons, particularly so for women and younger and middle aged adults.