Background: Internet use has become an integral part of our daily lives, especially for college students whose learning and social interactions involve extensive use of the Internet, which places them at high risk for Internet addiction (IA). A variety of negative health and social consequences have also been reported to be associated with IA; yet, little is known about the relationships between IA and health-related quality of life (HRQOL) among college students. Objectives: To empirically examine the relationships of IA and IA behavioral manifestations with HRQOL among college students in Taiwan. Methods: Data from a total of 1,452 college students were collected from a self-administered survey (response rate=90.8%), using the proportional stratified cluster sampling method. IA (including 5 IA behavioral manifestations) and HRQOL were assessed by the Chen Internet Addiction Scale (CIAS) and the World Health Organization Quality of Life (WHOQOL-BREF) Taiwan version, respectively. To adjust for potential confounding effects, the multivariate linear regression analyses also accounted for participants’ background characteristics, health conditions (ADHD, depression, diagnosed physical and mental disorders), and risk behaviors. Results: The mean domain score of WHOQOL-BREF was 12.49 (SD = 1.78) in physical health, 13.16 (SD = 2.39) in the psychological domain, 13.55 (SD = 2.22) in social relationships, and 14.07 (SD = 1.96) in the environment domain. Multivariate analyses indicated that IA was significantly associated with all 4 domains of HRQOL (β = -.130, -.147, -.103, -.085, respectively), after controlling for potential confounding factors. Further, IA behavioral manifestations such as compulsivity, interpersonal and health problems, and time management problems were found significantly associated with decreased HRQOL in physical health (β=-.096, -.100, -.083, respectively); compulsivity was also negatively associated with HRQOL in the psychological (β=-.166) and environment (β=-.163) domains; lastly, interpersonal and health problems significantly affected HRQOL (β=-.088) in social relationships. Severity of depression had the strongest negative effects on HRQOL across all 4 domains. Conclusions: This study demonstrated that IA has impacted all aspects of HRQOL among college students and further illustrated how various IA behavioral manifestations might affect HRQOL in different domains. Considering that Internet use has permeated into our daily lives, more research is warranted to illuminate the mechanisms of how IA affects our HRQOL, and to facilitate the development of effective intervention programs to prevent the negative consequences of Internet misuse.