To assess the prevalence and factors associated with fatigue in the general population.Population-based, cross-sectional survey performed between May 2014 and April 2017.General population of the city of Lausanne, Switzerland.2848 participants (53.2% women, age range 45-86 years).Prevalence of fatigue the previous week, defined as a score of ≥4 using the Fatigue Severity Scale.The prevalence of fatigue was 21.9% (95% CI 20.4% to 23.4%) in the total sample. On bivariate analysis, participants with fatigue were younger, had a higher body mass index, a lower handgrip strength and lower ferritin levels. Participants with fatigue were more frequently women, had a lower educational level, presented more frequently with clinical insomnia, diabetes, anaemia, depression and low thyroid stimulating hormone (TSH) values, had a higher consumption of antihistamines, antidepressants and hypnotics, and rated more frequently their health as bad or very bad. Multivariable analysis showed that obesity (OR 1.40 (95% CI 1.03 to 1.91)), insomnia categories (p value for trend <0.001), depression (OR 3.26 (95% CI 2.38 to 4.46)), anaemia (OR 1.70 (95% CI 1.00 to 2.89)) and low self-rated health status (p value for trend <0.001) were positively associated with fatigue, while older age (p value for trend 0.002) was negatively associated with fatigue. Conversely, no association was found for diabetes, TSH levels, antihistamines or hypnotics.In a population-based sample aged 45-86, fatigue was present in one out of five subjects. Regarding clinical factors, sleep disturbances such as insomnia and sleep apnoea should be assessed first, followed by depression. Regarding biological factors, anaemia should be ruled out, while screening for hypothyroidism is not recommended as a first step. Sleep complaints and fatigue in older subjects are not due to ageing and should prompt identification of the underlying cause.