To analyze possible factors associated with the quality of life (QoL) of mothers of preterm infants with very low birth weight (VLBW) during the first 3 years after delivery. The World Health Organization Quality of Life (WHOQOL)-bref scores were compared and correlated with maternal and infant-related sociodemographic and clinical variables at maternal discharge (T0) and at 6 (T1), 12 (T2), 24 (T3), and 36 (T4) months after delivery. Multiple linear regression models were fitted to investigate the effect of these variables on the mothers' QoL. The WHOQOL-BREF physical domain scores were higher at T1 and T2 compared to T0 (p = 0.013). Maternal variables that contributed to maternal QoL scores (p < 0.05) were stable marital union (b = 13.60; T0), family income (b = -12.75; T3), Evangelical religion (b = 8.11; T4), and beck depression inventory (BDI) score (-1.42 ae b ae -0.36; T0, T1, T2, T3, and T4). Infants' variables that most affected maternal QoL (p < 0.05) were posthemorrhagic hydrocephalus (PHH) (-18.84 ae b ae -10.05; T1, T2, and T4), bronchopulmonary dysplasia (BPD) (b = -7.41; T2), female gender (b = 8.09; T2), and SNAPPE severity score (b = -0.23; T3). Mothers of preterm infants with VLBW exhibited transient improvements in physical well-being during the first year after delivery. The presence of depressive symptoms in mothers and the diagnosis of PHH or BPD were negatively associated with QoL. Social, religious, and economic aspects were also important factors for the QoL of mothers of preterm infants with VLBW.