Summary Objective To determine the risk of venous thromboembolism (VTE) associated with prolonged work- and computer-related seated immobility. Design Case-control study in which cases were patients aged 18–65 years attending outpatient VTE clinics, and controls were patients aged 18–65 years admitted to CCU with a condition other than VTE. Interviewer-administered questionnaires obtained detailed information on VTE risk factors and clinical details. Setting VTE Clinics and Coronary Care Unit (CCU), Wellington and Kenepuru Hospitals, Wellington between February 2007 and February 2009. Main outcome measure The relative risk of VTE associated with prolonged work- and computer-related seated immobility, defined as being seated at work and on the computer at home, at least 10 hours in a 24-hour period and at least 2 hours at a time without getting up, during the four weeks prior to the onset of symptoms that led to VTE diagnosis or CCU admission. Results There were 197 cases and 197 controls. Prolonged work- and computer-related seated immobility was present in 33/197 (16.8%) and 19/197 (9.6%) cases and controls, respectively. In multivariate analyses, prolonged work- and computer-related seated immobility was associated with an increased risk of VTE, odds ratio 2.8 (95% CI 1.2–6.1, P=0.013). The maximum and average number of hours seated in a 24-hour period were associated with an increased risk of VTE, with odds ratios of 1.1 (95% CI 1.0–1.2, P=0.008) and 1.1 (95% CI 1.0–1.2, P=0.014) per additional hour seated. Conclusion Prolonged work- and computer-related seated immobility increases the risk of VTE. We suggest that there needs to be both a greater awareness of the role of prolonged work-related seated immobility in the pathogenesis of VTE, and the development of occupational strategies to decrease the risk.