Context: Non-Hodgkin lymphomas (NHL) are one of the most diagnosed forms of lymphoproliferative diseases, of which diffuse large B-cell lymphoma is the most common form. According to the literature, NHL with primary involvement of the lymph nodes occurs in 52%–70% of patients, being the most common primary localization in NHL. Treatment opportunities for NHL have become increasingly heterogeneous, but the penetrability of many of them, especially targeted treatments, is low in low- to middle-income countries (LMICs). Objective: The aim of this study was to evaluate the therapeutic implication of the use of the targeted approach in combination with conventional chemotherapy in the treatment of nodal-onset NHL. Material and Methods: A retrospective study was performed, including 82 patients diagnosed with NHL and monitored at the Oncological Institute of the Republic of Moldova. Results: Eighty-two patients participated in the study, 39 of whom were men and 43 were women. The mean age of the patients was 56.02±13.8 years. NHL had its onset in the peripheral lymph nodes in 84.14% of patients, the mediastinal lymph nodes in 8.53%, and the abdominals in 7.31%. The majority of patients were diagnosed in generalized stages: 18 (21.95%) in stage III and 43 (52.43%) in stage IV. Localized stages were found in 25.6% of cases, with 7 (8.53%) stage I and 14 (17.07%) stage II cases. Aggressive NHLs were diagnosed in 53 (64.63%) patients, whereas indolent NHLs were diagnosed in 29 (35.36%) cases. Sixty-two (75.6%) patients received, as first-line therapy, the combination of rituximab+chemotherapy (subgroup 1; Sg1), and 20 (24.39%) patients received just conventional chemotherapy (subgroup 2; Sg2). The overall response rate (ORR) in Sg1 was 87.09% and 65.0% in Sg2. Complete remissions (CR) were achieved in 64.51% of patients in Sg1 and 45.0% of cases in Sg2. Progression-free survival (PFS) had a median of 20 months in Sg1 and 12 months in Sg2 (P=0.001) Conclusions: The use of targeted treatment with rituximab increased the ORR rate (87.09% vs. 65.0%), the frequency of CR (64.51% vs. 45.0%), and PFS (20 months vs. 12 months [P<0.05]).