Objective: Although studies have consistently indicated that among college students alcohol use and the likelihood of experiencing alcohol-related problems are related, it is possible that additional factors strengthen the magnitude of this relationship. The purpose of the present study was to assess the moderating effect of two such factors: negative affect and coping drinking motives. Method: Data were collected on 316 college students at a midsized, public university in the upper Midwest who reported using alcohol. Results: Findings indicated that both negative affect and coping drinking motives moderated the alcohol use-alcohol problems relationship. The three-way interaction indicated that the strongest relationship between alcohol use and alcohol-related problems existed for individuals high in both negative affect and coping drinking motives. Conclusions: This study suggests that college students high in negative affect and coping drinking motives are particularly at risk for experiencing problems as a result of their alcohol use, indicating that clinicians should consider screening for these factors when conducting alcohol-related prevention and intervention efforts.