Objective The present study aimed to explore how the patterns of interaction between stress and positive resources differ according to the severity of depression and which resources play the most important role among the various positive resources. Methods The study included 1,806 people who had visited a health screening center for a mental health check-up to evaluate the levels of perceived stress, positive resources, and depressive symptoms. The participants were divided into a depressive group (n=1,642, mean age 50.60, female 68%) and a non-depressive group (n=164, mean age 48.42, female 66.6%). We conducted hierarchical regression analyses and simple slope analyses to examine the interaction between perceived stress and positive resources. Results The interaction between perceived stress and optimism was significantly associated with depression in non-depressive groups. In depressive groups, the interactions between five types of positive resources (optimism, purpose in life, self-control, social support and care) and perceived stress were all significantly related to depression. Conclusion Interventions that promote optimism can be helpful for preventing inevitable stress from leading to depression. A deficiency in positive resources may be a factor in aggravating depression in stressful situations for people reporting moderate to severe depressive symptoms.