Introduction: Venous access is a crucial element in chemotherapy delivery. It remains unclear whether cancer patients prefer a port to a peripherally inserted central catheter (PICC). Our study aimed to assess cancer patients’ satisfaction with their venous access device and to compare the quality of life (QoL) of subjects with a PICC to those with a port. Methods: In this prospective cohort study, EORTC QLQ-C30, and a locally developed quality of life survey (QLAVD), designed to assess satisfaction with venous access devices, were administered to breast or colorectal cancer patients over a one-year period following the device insertion. Mixed effects models were used to assess changes on mean scores at different time points. Results: A total of 101 patients were recruited over a three-year period, (PICC group, n = 50; port group, n = 51). Survey response rates for months one and three were 72% and 48%, respectively. Overall, no significant differences were noted between the two groups in relation to EORTC QOL. At three months, the mean pain scores were 3.5 ± 2.3 for the port and 1.3 ± 0.75 for PICC (<0.001). The mean score for a negative effect of the venous access device on psychosocial well-being was 6.0 ± 4.1 for PICC and 3.0 ± 2.7 for the port (p = 0.005). Complications related to PICCs occurred in 38% patients versus 41% with a port (p > 0.24). Conclusions: Although subjects with a port experienced more pain during the device insertion or access for chemotherapy, it had a smaller negative impact on psychosocial scores than the PICC. No significant differences in complications rates were observed between the two devices.