Background: The safety profile of Targeted therapies (TT) and immunotherapy (IT) may be underestimated and negatively affect the clinical outcome. Methods: A nationwide, randomized, open-label trial (NCT04726020) conducted among 29 Italian centers involved two cohorts of 223 adult patients (pts) with a solid tumor, receiving TT (group B, 119 pts) or IT (group C, 104 pts). Pts were randomized to receive a weekly nurse monitoring phone call, together with an educational leaflet with some practical advice about toxicities (experimental arm), or only the educational leaflet (control arm). In the experimental arm, pts received their monitoring phone call before their treatment began, then every week for up to 16 weeks of treatment were completed. The primary objective was the evaluation of the difference in toxicities according to patient-reported outcome (PRO)-CTCAE. Results: Both arms were comparable in terms of pts’ characteristics (e.g. site of primary tumor, line of treatment). The adherence to the project (that is the completion of every expected call) was 62.1% in group B and 66.9% in group C. In group B, in the experimental arm, we found a higher number of pts without pain (53.7 vs 39.9%, p = 0.047); a trend of lower fatigue (29.2 vs 18%, p = 0.067) was also observed. In group C, a higher number of pts did not report fatigue (29.1 vs 17.5%, p = 0.043), shortness of breath (61.4 vs 38.5%, p = 0.002) or dry skin (72 vs 52.3%, p = 0.004). More pts also referred to be without pain (51.6 vs 38.8%, p = 0.065) and pruritus (75.9 vs 64.5%, p = 0.088), even if these difference were not statistically significant. Conclusions: The use of PRO assessment through active nurse monitoring might lead to a better tolerance of TT and IT with possible implications on pts’ quality of life and ultimately on treatment outcome. In particular, in the IT group, several symptoms were prevented from occurring, thus encouraging a major effort to implement such active monitoring in this population. Clinical trial information: NCT04726020.