Characteristics of diphenhydramine (DPH)-induced accidental overdose deaths were compared to deaths without DPH present. Data from 4702 drug-induced deaths during 2005 to 2011 in four states were reviewed, with 3884 of these certified as accidental. DPH was involved in 276 cases (5.9%), with the manner of death ruled accidental in 181 (DPH group). The remaining 3703 accidental deaths constituted the control group. Age, body mass index, and the cases with benzodiazepine or opioid co-intoxicants did not differ significantly between groups. In the DPH deaths, methadone was the most frequently identified additional co-intoxicant, particularly when only one or two other co-intoxicants were present. Significantly more females (57.5% vs. 31.5%, respectively) and co-intoxicants were present (55.8% vs. 20.1% with ≥ 3 other co-intoxicants present, respectively) in the DPH compared to the control group. Alcohol was identified significantly less often in DPH decedents. Antidepressants overall and the selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) classes appeared significantly more often as co-intoxicants in DPH decedents compared to controls. Female DPH decedents were also significantly more likely than control females to have antidepressants (32.7% vs. 16.8%, respectively), TCAs (16.4% vs. 7.1%), or SSRIs present (21.2% vs. 11.6%). DPH concentrations in the accidental deaths were usually lower compared to the suicides although overlap was present. In conclusion, the availability of over-the-counter DPH appears to pose significant potential for drug abuse and should be identified as contributory to death with other detected co-intoxicants such as antidepressants, benzodiazepines, opioids, and other central nervous system depressant drugs.