Objective: To understand the association between insomnia and HRQoL after statistically controlling for socio-demographic characteristics, health habits, BMI, a number of medical conditions, and the presence of depressive symptoms. Methods: A sample of primary care patients (18 to 64 years of age) in a large hospital outpatient clinic was mailed a survey packet that contained the MOS Short Form 36 (SF-36), and Insomnia Severity Index (ISI). These patients were selected based on their visit(s) to the clinic in the past six months and grouped into one of the following five groups: cardiovascular (CVD), diabetes (D), gastrointestinal (GI), musculoskeletal (MS), and obstructive airways diseases (OAD) based on the presence of diagnostic codes related to these chronic conditions in their medical records. Group differences in SF-36 domain scores were analyzed using ANOVA techniques. Results: Based on 1,020 responses (46.58% response rate), in patients with insomnia, mean SF-36 Physical Component Summary (PCS) scores were: CVD: 37.8 + 2.9; D: 37.6 + 3.9; GI: 45.3 + 2.9; MS: 32.4 + 3.2; OAD: 44.6 + 3.2. Mean Mental Component Summary (MCS) scores were: CVD: 39.2 + 2.6; D: 42.7 + 4.0; GI: 33.9 + 3.8; MS: 41.1 + 3.6; OAD: 41.1 + 3.8. In patients without insomnia PCS scores were: CVD: 47.0 + 2.4; D: 46.4 + 3.3; GI: 49.2 + 2.2; MS: 39.9 + 3.0; OAD: 51.7 + 2.9. In the same patients MCS scores were CVD: 47.5 + 2.1; D: 47.0 + 3.3; GI: 50.0 + 2.9; MS: 50.0 + 3.4; OAD: 45.0 + 3.4. In addition, SF-36 scores for all individual domains in patients with insomnia were lower than those of patients without insomnia across all disease groups. Conclusion: A significant independent relationship between insomnia and HRQoL remained even after controlling for all relevant potential confounders. No domain of HRQoL was disproportionately influenced by insomnia.