© 2019, Copyright © 2019 Baylor University Medical Center. Pembrolizumab, a monoclonal antibody against the immune checkpoint receptor–programmed cell death protein 1, has proven clinical efficacy in melanoma and other solid tumors. It increases the body’s immune response against the tumor cells. However, because of an uninhibited immune system, immune-mediated adverse effects can arise. Though most adverse effects from pembrolizumab involve the gastrointestinal tract, skin, and endocrine system, rheumatologic manifestations are not very well defined. We describe two cases of severe inflammatory arthritis and tenosynovitis, which are rare adverse effects of pembrolizumab. Increased awareness of this manifestation is imperative to establish the diagnosis and initiate timely treatment.