Background: New federal initiatives target funds toward chronically homeless as distinct from other homeless persons. Few data exist, however, to substantiate the implications of chronic homelessness for major health outcomes. Objectives: Using data from a 2-year cohort of addicted persons, we tested whether changes in mental and physical health-related quality of life (HRQOL) differed according to homeless chronicity. Methods: Using self-reported homelessness, we classified subjects as chronically homeless (CH; n = 60), transitionally homeless (TRANS; n = 108), or as housed comparison subjects (HSD; n = 106). The Short Form-36 Health Survey, administered at baseline and 2 follow-ups over a period of 2 years, provided a Mental Component Summary (MCS) and a Physical Component Summary (PCS) for HRQOL. Mixed model linear regression was used to test the association between housing status, MCS, and PCS. Additional models assessed whether medical, psychiatric, addiction, and social support measures could account for HRQOL differences. Results: All subjects had low MCS scores at study entry (mean, 31.2; SD, 12.6). However, there was a significant housing status-by-time interaction (P = 0.01). At final follow-up, CH and TRANS subjects had lower adjusted MCS scores than HSD subjects (33.4, 38.8, and 43.7 for the 3 groups, respectively; all P ≤ 0.01). By contrast, housing status and PCS were not significantly associated (P = 0.19). Medical, psychiatric, addiction, and social support variables had significant associations with MCS, and their inclusion in the regression reduced the apparent effect of housing status on MCS. Conclusions: Chronic homelessness was associated with especially poor mental but not physical HRQOL over time. These findings reinforce a new typology of homelessness. Copyright © 2005 by Lippincott Williams & Wilkins.