Objectives: Tedizolid and comparator agent in vitro activities were assessed against clinically relevant gram-positive pathogens causing pneumonia in patients in European and US hospitals. Tedizolid was approved in the United States, Europe, and other regions to treat adults with acute bacterial skin and skin structure infections (ABSSSIs) and is being evaluated for treating nosocomial pneumonia. Methods: A total of 6,019 unique clinical isolates deemed to be responsible for community-acquired (CAP) and healthcare-associated pneumonia (HCAP), including hospital-acquired (HAP) in hospitalized patients, were included. A separate analysis included the HAP subset. Isolates originated from 33 and 30 institutions in Europe and the United States, respectively, between 2014 and 2016. Results: No substantive differences in tedizolid MIC values were found for the different species/organism groups over time or by geographic region. Isolates causing HAP showed slightly decreased activity to comparator agents compared to CAP/HCAP isolates. Tedizolid (100.0% susceptible) showed MIC50/90 results of 0.12/0.12 mg/L (US) and 0.12/0.25 mg/L (Europe) when tested against S. aureus HAP isolates, regardless of methicillin susceptibility or year of isolation. Coagulase-negative staphylococci from the United States and Europe (MIC50, 0.12 mg/L) demonstrated identical MIC50 values for tedizolid. Tedizolid exhibited MIC50 results of 0.25 mg/L and 0.12 mg/L when tested against β-hemolytic streptococci and viridans group streptococci isolates, respectively, regardless of geographic region. Conclusions: Tedizolid had potent activity in vitro against this contemporary collection of European and US gram-positive pneumonia isolates that was sustained over a period of 3 years (2014–2016).