Objective To evaluate the factors associated with false negatives in RT-qPCR in patients with mild-moderate symptoms of COVID-19. Materials and methods This was a cross-sectional study that used a random sample of non-hospitalized patients from the primary care management division of the Healthcare Area of Leon (58 RT-qPCR-positive cases and 52 RT-qPCR-negative cases). Information regarding symptoms was collected and all patients were simultaneously tested using two rapid diagnostic tests – RDTs (Combined – cRDT and Differentiated – dRDT). The association between symptoms and SARS-CoV-2 infection was evaluated by non-conditional logistic regression, with estimation of Odds Ratio. Results A total of 110 subjects were studied, 52% of whom were women (mean age: 48.2 ± 11.0 years). There were 42.3% of negative RT-qPCRs that were positive in some RDTs. Fever over 38 °C (present in 35.5% of cases) and anosmia (present in 41.8%) were the symptoms most associated with SARS-CoV-2 infection, a relationship that remained statistically significant in patients with negative RT-qPCR and some positive RDT (aOR = 6.64; 95%CI = 1.33–33.13 and aOR = 19.38; 95% CI = 3.69–101.89, respectively). Conclusions RT-qPCR is the technique of choice in the diagnosis of SARS-CoV-2 infection, but it is not exempt from false negatives. Our results show that patients who present mild or moderate symptoms with negative RT-qPCR, but with fever and/or anosmia, should be considered as suspicious cases and should be evaluated with other diagnostic methods.