Here we describe our experience with a rare case of methotrexate (MTX)-associated lymphoproliferative disorder (LPD) initially diagnosed as follicular lymphoma (FL) and then in relapse as classic Hodgkin lymphoma (CHL). A 66-year-old man was admitted to the hospital with fever and abdominal and lower back pain after a transient remission of MTX-associated FL (MTX-FL) following MTX withdrawal. Computed tomography (CT) showed para-aortic lymphadenopathy, which was compatible with one of the previous FL lesions. We considered a relapse of FL and started bendamustine and rituximab. Although his initial symptoms and para-aortic lymphadenopathy regressed after the first course, he began to have dorsal pain, and multiple osteolytic lesions were detected on CT. We biopsied a Th4 vertebra osteolytic lesion, and the results indicated MTX-associated CHL (MTX-CHL). We successfully treated advanced MTX-CHL with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD). This case suggests the importance of repeat biopsy of a new lesion arising after resolution of previously affected sites in MTX-LPD and the effectiveness of A+AVD in treating advanced MTX-CHL.