Syndromes for which no physical or pathological changes can be found tend to be researched and managed in isolation although hypotheses suggest that they may be one entity. The objectives of our study were to investigate the co-occurrence, in the general population, of syndromes that are frequently unexplained and to evaluate whether they have common associated factors. We conducted a population-based cross-sectional survey that included 2,299 subjects who were registered with a General Medical Practice in North-west England and who completed full postal questionnaires (response rate 72%). The study investigated four chronic syndromes that are frequently unexplained: chronic widespread pain, chronic oro-facial pain, irritable bowel syndrome, and chronic fatigue. Validated instruments were used to measure the occurrence of syndromes and to collect information on a variety of associated factors: demographic (age, gender), psychosocial (anxiety, depression, illness behaviour), life stressors, and reporting of somatic symptoms. We found that 587 subjects (27%) reported one or more syndromes: 404 (18%) reported one, 134 (6%) reported two, 34 (2%) reported three, and 15 (1%) reported all four syndromes. The occurrence of multiple syndromes was greater than would be expected by chance (P < 0.001). There were factors that were common across syndromes: female gender [odds ratio (OR) = 1.8; 95% confidence interval (95% CI) 1.5-2.2], high levels of aspects of health anxiety like health worry preoccupation (OR = 3.5; 95% CI 2.8-4.4) and reassurance seeking behaviour (OR = 1.4; 95% CI 1.1-1.7), reporting of other somatic symptoms (OR = 3.6; 95% CI 2.9-4.4), and reporting of recent adverse life events (OR = 2.3; 95% CI 1.9-2.8). This study has shown that chronic syndromes that are frequently unexplained co-occur in the general population and share common associated factors. Primary care practitioners need to be aware of these characteristics so that management is appropriate at the outset.