OBJECTIVES: PatientsLikeMe developed the 24-item PLMQOL to be a brief, easy-to-complete online patient-reported assessment of health-related quality of life. The instrument consists of three domains: physical, social, and mental function. As part of the validation process, we examined the performance of the PLMQOL compared with the RAND SF-36 in a population of patients with chronic disease. METHODS: Both the PLMQOL and the RAND SF-36 were administered via internet to 2042 invited members of PatientsLikeMe, a novel health data-sharing website allowing patients to monitor multidimensional aspects of health and well-being. Patients were randomized to questionnaire order and were required to have filled out at least one PLMQOL in the 30 days prior to the Jun 9, 2011 survey deployment date in order to be eligible. RESULTS: 1228 patients opened the survey invitation, and 660 (54% of those who opened the invite; 32% of eligible sample) patients completed the survey over the 10-day window of availability. No significant differences were seen between the randomized samples by age, sex, condition, or response. Respondents represented approximately 100 chronic conditions; most commonly reported were multiple sclerosis (n=147), fibromyalgia (n=112), Parkinson’s disease (n=43), and amyotrophic lateral sclerosis (n=42). The PLMQOL demonstrated high reliability across domains of physical (11 items, α=0.940-0.944), mental (8 items, α=0.909-0.917, and social function (5 items, α=0.810-0.828). In addition, the PLMQOL was highly correlated with relevant domains of the RAND SF-36 as demonstrated by Pearson correlation: RAND physical function and PLMQOL physical function (r=0.838-0.855, p<0.001); RAND emotional well-being and PLMQOL mental function (r=0.832-0.852, p<0.001); RAND social function and PLMQOL social function (r=0.795-0.823, p<0.001). CONCLUSIONS: The PLMQOL is a reliable and valid instrument for online assessment of health-related quality of life, demonstrating high correlations with relevant domains of the RAND SF-36. Further research is required to assess disease-specific psychometric properties and clinical validity.