Despite the fact that important gender differences in drug and alcohol use have been previously reported, little research to date has focused on gender differences with regard to nonmedical prescription opioid use. This study preliminarily examined the presenting characteristics and correlates (e.g., age of onset, route of administration, motives for using, method of introduction) of men and women with prescription opioid dependence. Participants were 24 (12 men, 12 women) non-treatment seeking individuals at least 18 years of age with current (i.e., past 12 months) prescription opioid dependence who participated in an in-depth interview. The average age of onset of prescription opioid use was 22.2 years (SD = 8.5). In comparison to men, women were approximately six years older when they initiated prescription opioid use, but were only three years older when they began to use prescription opioids regularly (i.e., weekly), suggesting an accelerated course of disease progression among women. Over half of the sample (61.5%) endorsed chewing and almost half (45.8%) endorsed crushing and snorting prescription opioids. Men were significantly more likely than women to crush and snort prescription opioids (75.0% vs. 16.7%; p = 0.01). Women were significantly more likely than men to be motivated to use prescription opioids in order to cope with interpersonal stress, and to use them first thing in the morning (ps = 0.04). Concomitant alcohol and other drug use were common among both men and women. The findings highlight clinically relevant gender differences and may help enhance the design of gender-sensitive screening and treatment interventions for prescription opioids.