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Background and objective Postpartum depression (PPD) is a frequent maternal mental health disorder associated with adverse outcomes for both mothers and their children. Its burden may be particularly relevant in regions characterized by social vulnerability and limited access to specialized mental health services. Epidemiological data from southern Mexico remain scarce, especially in primary care settings where early identification is critical. The objective of this study is to estimate the prevalence of PPD among women attending a primary care unit in Salina Cruz, Oaxaca, Mexico. Methods A cross-sectional study was conducted among postpartum women attending a family medicine unit of the Instituto Mexicano del Seguro Social in Salina Cruz, Oaxaca. Postpartum depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale. Sociodemographic and obstetric variables were recorded. Prevalence was estimated with 95% CIs. Differences between women with and without probable PPD were explored using the chi-square or Fisher's exact test, as appropriate. Results A total of 120 postpartum women were included. The median age was 25.5 years (q25-q75: 20-32), and the median time from delivery to screening was six weeks (q25-q75: 4-6). The median EPDS score was 11 (q25-q75: 10-12). Using a cutoff score of ≥13, the prevalence of PPD was 21.7% (95% CI: 14.3-29.1). Cesarean section accounted for 65.0% of deliveries, and breastfeeding difficulties were reported by 59.2% of participants. Conclusions PPD was identified in approximately one in five women attending primary care in southern Mexico. In a referral setting serving a socioeconomically diverse population with limited access to specialized mental health services, this prevalence represents a clinically relevant and potentially underrecognized burden. Routine screening for PPD in primary care could facilitate earlier detection and improve access to timely mental health care.