Background: SARS-CoV-2 has drastically affected healthcare globally and causes COVID-19, a disease that is associated with substantial morbidity and mortality. We aim to describe rates and pathogens involved in co-infection or subsequent infections and their impact on clinical outcomes among hospitalized patients with COVID-19. Methods: Incidence of and pathogens associated with co-infections, or subsequent infections, were analyzed in a multicenter observational cohort. Clinical outcomes were compared between patients with a bacterial respiratory co-infection (BRC) and those without. A multivariable Cox regression analysis was performed evaluating survival. Results: A total of 289 patients were included, 48 (16.6%) had any co-infection and 25 (8.7%) had a BRC. No significant differences in comorbidities were observed between patients with co-infection and those without. Compared to those without, patients with a BRC had significantly higher white blood cell counts, lactate dehydrogenase, C-reactive protein, procalcitonin and interleukin-6 levels. ICU admission (84.0 vs 31.8%), mechanical ventilation (72.0 vs 23.9%) and in-hospital mortality (45.0 vs 9.8%) were more common in patients with BRC compared to those without a co-infection. In Cox proportional hazards regression, following adjustment for age, ICU admission, mechanical ventilation, corticosteroid administration, and pre-existing comorbidities, patients with BRC had an increased risk for in-hospital mortality (adjusted HR, 3.37; 95% CI, 1.39 to 8.16; P = 0.007). Subsequent infections were uncommon, with 21 infections occurring in 16 (5.5%) patients. Conclusions: Co-infections are uncommon among hospitalized patients with COVID-19, however, when BRC occurs it is associated with worse clinical outcomes including higher mortality.