Background Caring for an ill or disabled family member imposes a well-documented burden on the caregiver. The benefits of a health intervention may be underestimated if “spillover” effects on family members are not captured, resulting in inaccurate conclusions of economic evaluations. Objective To provide an estimate of, and to summarize measurement approaches for, the spillover disutility of illness on family members, relatives, and caregivers, through a systematic review of the literature. Methods The medical (PubMED), psychology (PsycINFO), and economics (EconLit) literatures were searched from inception through February 2012 for published studies measuring spillover disutility of illness on family members and caregivers. Inclusion criteria were (1) studies using preference-based measures of health-related quality of life, and (2) studies reporting spillover disutility, or (3) studies reporting data from which a spillover disutility could be inferred. Results Fifteen studies were included in this review: seven reported estimates of spillover disutility and eight reported data from which disutility could be inferred. Three studies found no disutility associated with spillover, whereas 12 found measurable effects as large as −0.718 (and two found evidence of positive spillover in subsets of their samples). Generic (indirect) utility instruments were primarily used to measure spillover, including the EQ-5D, QWB, and HUI ( n  = 13), though two studies used modified versions of the time trade-off technique. Illnesses studied included childhood disorders (e.g., spina bifida, congenital malformations), diseases of the elderly (e.g., Alzheimer’s disease and dementia), physically disabling conditions (e.g., arthritis, multiple sclerosis), and medical conditions such as cancer and stroke. The persons affected by spillover included parents, grandparents, spouses/partners, other family caregivers, and household members. Conclusions There is a limited literature on the spillover disutility of illness on family members and caregivers, providing some specific estimates of a generally small, negative effect for particular conditions and individuals. Measurement methods vary across studies and a consensus approach has not yet been reached. Evidence suggests that the inclusion of spillover effects in economic evaluations would increase the relative effectiveness of interventions that address conditions with spillover compared to those without, though such differential benefits may be limited to such specific circumstances.