The rapid expansion of online video gaming as a leisure time activity has led to the appearance of problematic online gaming (POG). According to the literature, POG is associated with different psychiatric symptoms (eg, depression, anxiety) and with specific gaming motives (ie, escape, achievement). Based on studies of alcohol use that suggest a mediator role of drinking motives between distal influences (eg, trauma symptoms) and drinking problems, this study examined the assumption that there is an indirect link between psychiatric distress and POG via the mediation of gaming motives. Furthermore, it was also assumed that there was a moderator effect of gender and game type preference based on the important role gender plays in POG and the structural differences between different game types.This study had two aims. The first aim was to test the mediating role of online gaming motives between psychiatric symptoms and problematic use of online games. The second aim was to test the moderator effect of gender and game type preference in this mediation model.An online survey was conducted on a sample of online gamers (N=3186; age: mean 21.1, SD 5.9 years; male: 2859/3186, 89.74%). The Brief Symptom Inventory (BSI), the Motives for Online Gaming Questionnaire (MOGQ), and the Problematic Online Gaming Questionnaire (POGQ) were administered to assess general psychiatric distress, online gaming motives, and problematic online game use, respectively. Structural regression analyses within structural equation modeling were used to test the proposed mediation models and multigroup analyses were used to test gender and game type differences to determine possible moderating effects.The mediation models fitted the data adequately. The Global Severity Index (GSI) of the BSI indicated that the level of psychiatric distress had a significant positive direct effect (standardized effect=.35, P<.001) and a significant indirect (mediating) effect on POG (standardized effect=.194, P<.001) via 2 gaming motives: escape (standardized effect=.139, P<.001) and competition (standardized effect=.046, P<.001). The comparison of the 2 main gamer types showed no significant differences in the model. However, when comparing male and female players it was found that women had (1) slightly higher escape scores (on a 5-point Likert scale: mean 2.28, SD 1.14) than men (mean 1.87, SD 0.97) and (2) a stronger association between the escape motive and problematic online gaming (standardized effect size=.64, P<.001) than men (standardized effect size=.20, P=.001).The results suggest that psychiatric distress is both directly and indirectly (via escape and competition motives) negatively associated with POG. Therefore, the exploration of psychiatric symptoms and gaming motives of POG can be helpful in the preparation of prevention and treatment programs.