Mixed infections of Cucumber mosaic virus (CMV), Potato virus Y (PVY), and CMV-satRNA in tomato are frequent in nature and exhibit different disease phenotypes that are the outcomes of synergistic and antagonistic interactions between the causative agents. Such mixtures of interactions make classic strains acquire new pathogenetic skills, which may change their eco-epidemiologic patterns. The emerging picture is very complex, and the present case study puts mixed infections into the framework of creating a more favorable condition for host-to-host aphid-mediated transmission of CMV and PVY. Field cases were reproduced in the tomato UC82 variety by using authentic mild and severe strains of CMV (namely, CMV-LS and CMV-Fny), a deletion mutant of CMV-Fny (namely, CMV-FnyΔ2b), a mild strain of PVY (PVY-SON41), and a benign variant of CMV-satRNA (namely, CMV-Tfn). PVY and either CMV strain acted synergistically in eliciting a disease pattern that was more severe than that produced by each virus in a single infection. The exacerbation of symptoms was particularly evident in the CMV-LS/PVY-SON41 combination; this may be attributable to a cumulative effect of the two silencing suppressors (i.e. 2b and HC-Pro proteins) encoded by the two viruses, respectively. The disease patterns observed with the different combinations of inoculum parallel the accumulation of viral RNAs in infected tissues. At single-cell level, and at early stages of infection, CMV took most of the advantage from the double infection with PVY, as the titer of its RNAs was increased while that of PVY was reduced. The two viruses seemed unable to invade the same cell—a condition that, at a later stage of infection, enabled the two viruses to be more uniformly distributed in tomato plant tissues. PVY-SON41 complemented movement defects of the CMV-FnyΔ2b deletion mutant, while CMV Tfn-satRNA reduced the antagonism of CMV-Fny vs PVY-SON41 by the downregulation of its RNA. The results of this work are relevant from an ecologic and epidemiologic perspective due to the frequency of natural mixed infection of CMV and PVY in tomato.