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Poor self-rated health (SRH) is associated with various adverse health outcomes, including cardiovascular disease. Little is known about SRH and health-related quality of life (HRQoL) as predictors of first-time venous thromboembolism (VTE). Our aim was to investigate the association between SRH, HRQoL, and risk of VTE in a whole cohort, as well as in women and men separately. A total of 108,025 middle-aged inhabitants (51 % women) of Västerbotten, Sweden, participated in a health examination between 1985 and 2014. Data on SRH, HRQoL, and potential confounders were collected by questionnaire. Participants were followed as a cohort and validated first-time VTE events were registered. The mean follow-up time was 13.9 years, during which 2054 participants experienced a first-time VTE. Overall, 27 % of participants reported their health as very good, 46 % as good, 20 % as average, 5 % as somewhat bad, and 1 % as bad. In a multivariable analysis, compared with participants who self-rated as having very good SRH, hazard ratios (95 % confidence intervals) for VTE were 1.17 (1.02–1.33) with good SRH, 1.27 (1.09–1.47) with average SRH, and 1.48 (1.00–2.18) with bad SRH. The risk of VTE increased with lower SRH for both men (p for trend 0.02) and women (p for trend 0.04). In a fully adjusted model, we also found significant associations between four aspects of HRQoL (general health, bodily pain, vitality, emotional well-being) and VTE risk. In conclusion, lower perceived health is associated with an increased risk of VTE in both men and women.