There is increased interest in developing multidisciplinary ambulatory care models of service delivery to manage patients with complex chronic diseases. These programs are expensive and given limited resources it is important that care is targeted effectively. One potential screening strategy is to identify individuals who report the greatest decrement in health related quality of life (HRQoL) and thus greater need. The aim of this study was to explore the relationship between HRQoL, comorbid conditions and acute health care utilisation.A prospective, longitudinal cohort design was used to evaluate the impact of HRQoL on acute care utilisation rates over three-years of follow-up. Participants were enrolled in chronic disease management programs run by a metropolitan health service in Australia. Baseline data was collected from 2007-2009 and follow-up data until 2012. Administrative data was used to classify patients' primary reasons for enrolment, number of comorbidities (Charlson Score) and presentations to acute care. At enrolment, HRQoL was measured using the Assessment of Quality of Life (AQoL) instrument, for analysis AQoL scores were dichotomised at two standard deviations below the population norm.There were 1999 participants (54 % male) with a mean age of 63 years (range 18-101), enrolled in the study. Participants' primary health conditions at enrolment were: diabetes 915 (46 %), chronic respiratory disease 463 (23 %), cardiac disease 260 (13 %), peripheral vascular disease, and 181 (9 %) and aged care 180 (9 %). At 1-year multivariate logistic regression models demonstrated that AQOL utility score was not predictive of acute care presentations after adjusting for comorbidities. Over 3-years an AQoL utility score in the lowest quartile was predictive of both ED presentation (OR 1.58, 95 % CI, 1.16-2.13, p = 0.003) and admissions (OR 1.67, 95 % CI.1.21 to 2.30, p = 0.002) after adjusting for differences in age and comorbidities.This study found that both HRQoL and comorbidities were predictive of subsequent acute care attendance over 3-years of follow-up. At 1-year, comorbidities was a better predictor of acute care representation than HRQoL. To maximise benefits, programs should initially focus on medical disease management, but subsequently switch to strategies that enhance health independence and raise HRQoL.