Background: The psychological distress is a kind of mental stress that people experience due to various causes. This study was performed aimed to investigate the psychological distress in cancer patients.Methods: This cross-sectional study was performed during one year on the patients who referred to two academic hospitals of Mashhad University of Medical Sciences for treatment or follow-up. Psychological distress questionnaire was used to collect data. Results were analyzed using SPSS version 16. P <0.05 was considered significant.Results: The mean (±SD) age of participants was 54 ± 15.30 with a range from 18 to 89. The most common cancers were colorectal, gastro-esophageal and breast cancer. The mean distress thermometer score was 5 ± 2.99. Out of 256, 173 (67.7%) of patients scored 4 or higher. The distress thermometer scores were higher among females, rural residents, those receiving treatment within the month before, patients with insight of their illness, those with low level of education and low functional status, non-smokers and divorced patients. Among these, having insight of the illness, receiving treatment in the month before and low functional status were significantly related with the psychological distress score. The most prevalent cause of psychological distress among the participants was fatigue, being reported by 176 participant (68.8%), followed by pain (59.4%), difficulty in transportation (59.4%), anxiety (57.2%), sadness (50.4%), anger (44.5%), and depression (43.8%). Conclusion: Due to higher rate of severe emotional distress in different types of cancer, particularly in women, rural patients, those with lower educational status and performance and also divorced and addicted people, it is important to pay more attention to these groups for decreasing emotional distress. It required supportive and relief measures including psychological methods and reducing pain to improve the performance of these patients.