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Early mother-infant interactions provide the foundation for developing self-regulation and healthy mother-infant relationship quality. During these interactions, mothers and infants mutually elaborate on and adjust their behaviours according to the behaviours of the other. This dynamic process is known as co-regulation (Fogel, 1993). Maternal depression is a risk-factor that may impede mother-infant interaction quality (Cohn et al., 1990; Jameson et al., 1997). Extending previous literature, this study compared co-regulation in mother-infant dyads with and without maternal depression at four months post-partum. Examining dyadic co-regulation early in infancy is essential as early interactions lead to recurring patterns and expectations that shape socio-emotional functioning throughout development (Fogel, 1993). This study also examined whether brief periods of maternal physical and emotional unavailability impact co-regulation differently depending on maternal depression status. The objectives were two-fold: (1) examine whether maternal depression status affects mother-infant co-regulation, and (2) whether experimentally induced perturbations would differentially impact co-regulation in depressed vs. non-depressed dyads. Using a mixed-design, 39 mothers (Mage = 25.56, SD = 6.33) and their four-month-old infants (19 males) participated in a series of laboratory-based tasks. The Center for Epidemiological Studies Depression Scale and cut-off criterion were used (CES-D; Randloff, 1977) to determine depressed or non-depressed status (see Field et al., 2005 for a similar method). Participants were video-taped during the widely used Still-Face (SF) Procedure (Tronick et al., 1978) and/or the Separation (SP) Procedure (Field et al., 1986). There were six 90-second periods. The SF comprised of (1) a period of unstructured face-to-face play, (2) a period in which mothers remained unresponsive and expressionless, and (3) a reunion period in which mothers were free to resume playing. The SP procedure was identical except during the second period the mother hid behind a screen to induce physical unavailability. Co-regulation was observationally coded using Fogel’s (2003) Revised Relational Coding System during the two play and reunion periods. Multivariate ANOVAs revealed that collapsed across all four periods, depressed dyads showed significantly less mutual engagement/activity levels (i.e., symmetrical co-regulation) and spent more time with one relationship partner disengaging from the interaction (i.e., unilateral co-regulation). Conversely, non-depressed dyads spent more time in back-and-forth exchanges characterized by mutual engagement and activity levels. Together these results suggest that maternal depression may negatively impact coordinated interactions between mothers and their infants. Conversely, the SF and SP perturbations did not have significant effects on the observed co-regulation patterns; although differences between the groups were larger following the period of emotional unavailability these differences did not reach statistical significance. Taken together, infants of non-depressed mothers may learn to rely on their mothers as reliable regulators of their emotional and behavioral experiences, thus improving the dyad’s ability to overcome/repair relationship perturbations and re-engage in their typical co-regulatory processes. Conversely, depressed dyads are more likely to disengage during mother-infant interactions and this is true even after exposure to situations that are somewhat stressful for most infants. Our results have implications for early identification of mother-infant dyads who may be at risk for atypical socio-emotional development and relationship quality.