Objective: This study examined the relationship between the number of comorbidities and health-related quality of life (HRQoL) and between select physical conditions and HRQoL. Differences in HRQoL in comparison to a normative sample were also examined.

Method: A cross-sectional study among people with multimorbidity (n = 401) attending a community-based, interdisciplinary health clinic was conducted. HRQoL was measured using the eight dimensions of the SF-36. Multiple linear regression and t-tests were used to analyse the data.

Results: A downward trend in HRQoL continued from 2 to 14 concurrent comorbidities. Patients with a higher number of comorbidities reported greater deficits in HRQoL, when age, gender, education and perceived social support were controlled for (beta = −0.11 to −0.31). The impact of the number of comorbidities was greatest for the bodily pain dimension of the SF-36 (beta = −0.31). Deficits were greatest for people with gastrointestinal conditions and back pain or sciatica. Moderate to large deficits in HRQoL compared to a normative population were found (Cohen’s d = 0.54–1.16).

Discussion: Understanding associations between the number and type of physical comorbidities and HRQoL may assist clinical services to design broad but targeted interventions to optimize HRQoL in this group of people.