Objective To investigate the clinical characteristics of pemetrexed-associated edema and to provide insights for its clinical management. Methods A retrospective analysis was conducted on cases of pemetrexed-induced edema. Data were collected from the China Hospital Pharmacovigilance System (CHPS) between November 1, 2021, and April 1, 2024, and supplemented by a systematic literature review of CNKI, Wanfang, VIP, and PubMed databases (up to April 2024). Extracted clinical data included patient demographics, pemetrexed indications, concomitant medications, edema characteristics (location and severity), time to onset, clinical interventions, and outcomes. Results A total of 24 patients were included. The cohort comprised 12 males and 12 females (each 50.0%), with a median age of 63 years (range: 39~77). Pemetrexed was administered as monotherapy in 8 cases and in combination with other antineoplastic agents in 16 cases. Edema involved multiple sites (≥2) in 10 patients (41.7%) and a single site in 14 patients (58.3%). The severity was graded as Ⅰ, Ⅱ, and Ⅲ in 4 (16.7%), 15 (62.5%), and 5 (20.8%) patients, respectively. The median time from pemetrexed initiation to edema onset was 105 days (IQR: 63~194.25), corresponding to a median of 5 treatment cycles (IQR: 3~9.25). The incidence of Grade Ⅲ edema was numerically higher in patients receiving pemetrexed with platinum-based agents (36.4%) than in those receiving non-platinum combinations (0.0%), though this difference was not statistically significant ( χ2=2.424, P=0.119). Similarly, the combination therapy group showed a higher incidence of Grade Ⅲ edema than the monotherapy group (25.0% vs. 12.5%; χ2=0.505, P=0.477). Edema improved in all 17 patients with documented outcomes. Conclusion Pemetrexed-associated edema primarily manifests in the lower limbs and eyelids, typically occurring after 4 cycles of chemotherapy. The risk of severe edema may be increased when pemetrexed is used in combination with other drugs, particularly platinum agents. Discontinuation of pemetrexed or administration of steroids may be effective in alleviating the symptoms.