Background: Non-medical use of prescription drugs (NMUPD) refers to the use of prescription drugs which are traditionally utilized to manage pain or treat psychiatric problems but without a doctor’s prescription. In 2010, an investigation by the Substance Use and Mental Health Services Administration (SAMHSA) revealed that 5.3% of young adults (18 to 25-year-olds) in the United States reported past-month NMUPD. NMUPD has become a growing concern owing to associations with consequences such as college dropout, poor academic achievement, and health jeopardizing behaviors. College students' NMUPD has been well documented in the United States. Limited studies, however, have been conducted among college students in China. The purposes of this study are to examine the prevalence and motives of NMUPD among college students in China, and to assess its relationship with stress (i.e., perceived stress and traumatic events), mental health problems (depression, anxiety, and post-traumatic stress disorder (PTSD)), utilization of healthcare, cultural orientation, and protective factors (i.e., resilience and future orientation). Methods: In Jan-April 2017, online data were collected using SONA system from a total of 720 undergraduates at Beijing Normal University (BNU) and University of Macau (UM) with an average age of 19.65. All participants reported their nonmedical use of prescription drugs (i.e., opioids, sedatives, stimulants, and anxiolytics) in their lifetime and the past three months, stress, mental health, utilization of healthcare, cultural orientation, and protective factors. Spearman’s rank-order corrections and logistic regression were employed for statistical analyses. Results: Findings indicate that 41.2% of Chinese students reported taking prescription drugs without a doctor’s prescription. The most commonly misused prescription drugs were opioids (40.5% lifetime use, 31.8% past-three-months use), followed by sedatives (1.8% lifetime, 0.8% past 3 months), anxiolytics (0.9% lifetime,0 .3% past three months), and stimulants (0.2% lifetime, 0% past three months). Bivariate analyses suggest significantly positive correlations of lifetime NMUPD with mental health problems (anxiety and PTSD), cultural orientation (individualism and collectivism), and utilization of healthcare (frequency of healthcare use, time spent for healthcare, and money spent for healthcare). Similar results were found in terms of past-three-month NMUPD. The results of logistic regressions indicate the significant association of lifetime NMUPD with individualism of cultural orientation, and frequency of healthcare use. Specially, individualism, frequency of healthcare use, and time spent for healthcare were found to be associated with lifetime opioid misuse, and depression was significantly associated with sedative misuse. Resilience was negatively associated with lifetime sedative misuse. Frequency of healthcare use was also found to be positively associated with past-three-month opioid misuse. Conclusion: Utilization of healthcare, cultural orientation, and mental health problems appear to be the factors associated with NMUPD among college students at BNU and UM. More discussion is needed in Chinese society about regulation of prescription drug use. Future culturally-tailored prevention intervention programs may be beneficial to reduce the risk of NMUPD among Chinese college students.