Social stress, especially dyadic conflict among couples, is an important correlate of addiction. Several authors have suggested that the neuropeptide oxytocin (OT) may be useful in the treatment of couples with substance misuse. However, the literature examining OT among couples is scant and has yielded mixed findings. The current study examined the effects of OT versus placebo on emotional (e.g., warmth and anger) and physiological (e.g., skin conductance and heart rate) reactivity to a conflict resolution task in 30 heterosexual couples (N = 60) in which one or both members misused substances. Using a randomized, double-blind, and placebo-controlled design, both partners within each dyad were randomized to the same treatment condition. Participants completed a standardized conflict resolution task at baseline and 45 min following drug self-administration. Physiological measures were examined continuously during the laboratory tasks, and emotional reactivity was self-reported at baseline and at five time points over the course of 1 hr following the second conflict resolution task. Results of a multilevel growth curve model accounting for baseline scores, gender, and drug condition indicate that positive emotional experiences and skin conductance measures increased over the five time points. Neither drug condition nor gender was significantly related to outcomes, and no interaction effects were observed. These findings highlight the complexities involved in translational OT research and suggest that the impact of OT on key outcomes requires further exploration in regards to OT’s potential therapeutic benefit.