Drosophila has six receptor protein tyrosine phosphatases (RPTPs), five of which are expressed primarily in neurons. Mutations in all five affect axon guidance, either alone or in combination. Highly penetrant central nervous system (CNS) and motor axon guidance alterations are usually observed only when specific combinations of two or more RPTPs are removed. Here, we examine the sixth RPTP, Ptp4E, which is broadly expressed.Ptp4E and Ptp10D are closely related type III RPTPs. Non-drosophilid insect species have only one type III RPTP, which is closest to Ptp10D. We found that Ptp4E mutants are viable and fertile. We then examined Ptp4E Ptp10D double mutants. These die before the larval stage, and have a mild CNS phenotype in which the outer longitudinal 1D4 bundle is frayed. Ptp10D Ptp69D double mutants have a strong CNS phenotype in which 1D4 axons abnormally cross the midline and the outer and middle longitudinal bundles are fused to the inner bundle. To examine if Ptp4E also exhibits synthetic phenotypes in combination with Ptp69D, we made Ptp4E Ptp69D double mutants and Ptp4E Ptp10D Ptp69D triple mutants. No phenotype was observed in the double mutant. The triple mutant phenotype differs from the Ptp10D Ptp69D phenotype in two ways. First, the longitudinal tracts appear more normal than in the double mutant; two or three bundles are observed, although they are disorganized and fused. Second, axons labelled by the SemaIIB-tauMyc marker often cross in the wrong commissure. We also examined motor axon guidance, and found that no phenotypes are observed in any Ptp4E double mutant combination. However, triple mutants in which Ptp4E Ptp10D was combined with Ptp69D or Ptp52F exhibited stronger phenotypes than the corresponding Ptp10D double mutants.Type III RPTPs are required for viability in Drosophila, since Ptp4E Ptp10D double mutants die before the larval stage. Unlike Ptp10D, Ptp4E appears to be a relatively minor player in the control of axon guidance. Strong phenotypes are only observed in triple mutants in which both type III RPTPs are eliminated together with Ptp69D or Ptp52F. Our results allow us to construct a complete genetic interaction matrix for all six of the RPTPs.